The Pediatric Glaucomas

Author: Anil Mandal | Peter Netland

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An imprint of Elsevier Inc. © 2006, Elsevier Inc. All rights reserved. First published 2006 No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the Publishers. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, USA: telephone: (+1) 215 239 3804; fax: (+1) 215 239 3805; or, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Support and contact’ and then ‘Copyright and Permission’. ISBN 0 7506 7336 2 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress

Notice Medical knowledge is constantly changing. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this publication. The Publisher

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Foreword When I ﬁrst joined Robert Shaffer, MD and John Hetherington, MD in practice over 30 years ago, Dr Shaffer asked me if I would be interested in focusing on children with glaucoma. He had worked with Dr Barkan and had already developed a large practice in childhood glaucoma, especially the developmental form. That started a long-term interest in this fascinating, rewarding and sometimes discouraging disease. At one point we were seeing as many as one new case a week, which kept us all quite busy. I still see occasional patients on whom I operated 30 years ago who are seeing well and doing ﬁne. That is very gratifying. As most young physicians, I started out focused on managing the disease but it soon became obvious that managing the family was equally important. Parents of children with developmental glaucoma are often ﬁlled with guilt, believing that something they did or did not do caused this terrible affliction that could blind their child. Solving the problem is, of course, the best solution, but helping the parents understand that they are blameless and that the most important thing they can do for their child is to give them lots of love is critical. Some of these patients will inevitably end up blind and they will function much better in the world if they grow up in a loving environment. Occasionally, after multiple surgeries and continued visual deterioration, the doctor and the parents are faced with the

difﬁcult decision of whether to keep trying. Is the pain and risk of another operation worth it? A psychologist told me many years ago that a child who retains vision till the age of six or beyond will have visual memories that improve his later functioning. These points are nicely made in the conclusion to Chapter 10. Fortunately, these decisions are less common with the advent of antiﬁbrosis agents and drainage implants. At some point however, it may be best to quit. The parents will have to be led to this most difﬁcult decision by the physician. Finally, experience counts. It is often the ﬁrst operation that determines the outcome in these children and whenever possible it should be done by an experienced surgeon or team. Since these tend to be rare cases and patients cannot always travel, that will not always be possible. This book will help physicians manage the process of doing the right thing for the right diagnosis at the right time. I offer my congratulations and thanks to Drs Mandal and Netland for providing all this information in a wonderfully organized and illustrated text that clariﬁes the diagnosis and treatment of the many forms of childhood glaucoma. I wish it had been available 35 years ago.

H. Dunbar Hoskins, Jr MD

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Preface The idea for this book originated from patient care. The effort to manage the clinical problems in children with glaucoma revealed the need for up-to-date and organized information about the topic. Over the years, we have met and discussed these problems at length. Our previous writings provided the backbone for this work. We organized our material for an Instruction Course at the American Academy of Ophthalmology, which crystallized our thoughts about the topic. We have attempted to present evidence-based information about the topic, while providing perspectives from clinical experiences. Other excellent textbooks have appeared in the

past, but are sufﬁciently outdated to create a need for this book. Signiﬁcant advances have occurred in genetics, medical therapy, surgical management, and other topics included here. This book is intended for clinicians who care for pediatric glaucoma patients, including, in particular, glaucoma and pediatric subspecialists. We hope that other practitioners who have contact with pediatric glaucoma patients will ﬁnd value in it, and that ophthalmology residents and subspecialty trainees will beneﬁt from this information. Anil K. Mandal, MD Peter A. Netland, MD, PhD

Drs Mandal and Netland perform Koeppe gonioscopy during an examination under sedation.

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Acknowledgments We are deeply indebted to our patients, as well as our patients’ parents and families. Caring for these patients has been a group effort, and we appreciate all of the individuals on the ‘team.’ We are also grateful to our families, friends, mentors, and colleagues who provided support and guidance. Medical Publisher Karen Oberheim provided critical early support for the project, as did Senior Editor Natasha Andjelkovic and Assistant Editor Andrea P. Sherman. Joseph Mastellone and Stephen Moser assisted with photography. Jerry Harris at St. Jude Children’s Research Hospital provided assistance with graphic arts. We are especially thankful for the expert assistance of Mary E. Smith, Vijaya K. Gothwal, Anita Fernandez and Joyce Solomon. We thank Richard D. and Gail S. Siegal for their support. We would like to thank the copyeditor, Alison Woodhouse, the proofreader, J. Ian Ross, the indexer, Liza Furnival, and the illustrator Richard Tibbitts. Elsevier provided excellent publishing support through the efforts of Senior Editor Paul Fam, Project Development Manager Amy Head, Project Manager Kathryn Mason, Designer Andy Chapman, Illustration Manager Mick Ruddy and Product Managers Lisa Damico and Gaynor Jones.

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To my loving parents, Jayalaxmi and Manik, who instilled in me the desire to learn and the enjoyment of teaching and my wife, Vijaya, for her constant help and encouragement in this endeavour. Anil K. Mandal

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To my patients and their families, my colleagues and trainees, and my supportive family and friends. Peter A. Netland

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Light, my light, the world-ﬁlling light, the eye-kissing light, heart-sweetening light! Ah, the light dances at the center of my life... The butterflies spread their sails on the sea of light. Lilies and jasmines surge up on the crest of the waves of light. The light is shattered into gold on every cloud and it scatters gems in profusion. Mirth spreads from leaf to leaf and gladness without measure. The heaven’s river has drowned its banks and the flood of joy is abroad. From Gitanjali, Number 57 Rabindranath Tagore, Nobel Laureate 1913

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Chapter 1 Historical perspective of developmental glaucomas Introduction Goniotomy Description of the clinical entity Microsurgery and trabeculotomy

Introduction Congenital enlargement of the eye has been recognized since the time of Hippocrates (460–377 BC), Celsus (1st century AD), and Galen (130–201 AD), although buphthalmos or hydrophthalmos were not related to elevated intraocular pressure until the middle of the 18th century. Increased intraocular pressure was mentioned by Berger (1744), but was grouped together with a variety of heterogenous conditions varying from high myopia to anterior staphyloma and anterior megaophthalmos. In 1869, Von Muralt (1869) established the classical type of buphthalmos within the family of glaucoma. Both he and Von Graefe (1869) considered that the enlargement of the cornea was the primary phenomenon, but believed that the clinical picture with its rise of tension was due to a primary intraocular inflammation. Pathological studies of the late 1800s and early 1900s had detected congenital anomalies in the anterior chamber angle or the absence of Schlemm’s canal. These anomalies were conﬁrmed by Von Hippel (1897), Parsons (1904), and Siegrist (1905). Exhaustive anatomical descriptions appeared in the early to middle 1900s by Gros (1897), Reis (1905–11), Seefelder (1906–1920), and others who demonstrated a number of different malformations of the angle structures as the primary abnormality, with inflammation playing a secondary role.

The poor prognosis of infantile glaucoma changed dramatically in 19382 with the introduction of goniotomy (Greek: gonio = angle + tomein = to cut) by Otto Barkan (Fig. 1.1) who revived the Italian surgeon de Vincentis’ operation (1892), which ‘incised the angle of the iris in glaucoma.’ Otto Barkan modiﬁed de Vincentis’ operation by using a specially designed glass contact lens to visualize angle structures while using a knife to create an internal cleft in the trabecular tissue.3 He called the operation goniotomy and reported several successfully treated cases in congenital glaucoma.4,5 Although instrumentation has since been reﬁned and the operating microscope now permits more precise visualization of the angle structures, the operation has remained essentially unchanged. In 1949, Barkan described a persisting fetal membrane overlying the trabecular meshwork.5 This was conﬁrmed by Worst (1966) who termed it ‘Barkan’s membrane.’6 Recent pathological studies by Anderson,7–9 Hansson,10 Maul and co-workers,11 and Maumenee12 could ﬁnd no evidence of a membrane in any of the specimens they examined by light or electron microscopy. Despite this evidence, Worst stated that ‘though histopathological proof of this structure is almost completely lacking . . . this has little influence on the probability that this concept is valid.’13

Goniotomy As late as 1939, Anderson1 saw little hope for preservation of useful vision in these patients. Despite a detailed evaluation of all known treatment modalities available at that time, he stated that ‘one seeks in vain for a best operation in the treatment of hydrophthalmia.’ He further wrote: The future of patients with hydrophthalmia is dark. Little hope of preserving sufﬁcient sight to permit the earning of a livelihood can be held out to them. It progresses, as a rule, in a relentless fashion until the best setting for the patient is some institution that caters for the blind.

Figure 1.1 Otto Barkan (1887–1958). Reprinted with permission from Cordes FC, Otto Barkan, MD. Trans Am Ophthalmol Soc 1958; 56:3–4.

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Historical perspective of developmental glaucomas

Description of the clinical entity A few classic textbooks that have been written on the subject include Hydrophthalmia or Congenital Glaucoma (Anderson, 1939),1 Congenital and Pediatric Glaucomas (Shaffer and Weiss, 1970),14 and Glaucoma in Infants and Children (Kwitko, 1973).15 Sir Stewart Duke-Elder (1963) wrote: Buphthalmos (hydrophthalmos) is the condition wherein developmental abnormalities offer an obstruction to the drainage of the intra-ocular fluids so that the pressure of the eye is raised and a condition of congenital glaucoma results. The essential clinical feature of the anomaly is that the coats of the eye are of sufﬁcient plasticity to stretch under this increment of pressure with the results that the whole globe enlarges, producing an appearance which is said to resemble the eye of an ox.16 Primary congenital glaucoma was described by Shaffer and Weiss (1970) as a speciﬁc syndrome as follows: The most common hereditary glaucoma of childhood, inherited as an autosomal recessive pattern, with a speciﬁc angle anomaly consisting of absence of angle recess with iris insertion directly into the trabecular surface. There are no other major abnormalities of development. Corneal enlargement, clouding, and tears in Descemet’s membrane result from elevated intraocular pressure.14 Now it is ﬁrmly established that developmental glaucoma has as its hallmark fetal maldevelopment of the iridocorneal angle or goniodysgenesis.17 The anomalies of the angle include trabeculodysgenesis, iridodysgenesis, and corneodysgenesis, either singly or in some combination. The classic defect found in primary congenital glaucoma is isolated trabeculodysgenesis without any evidence of other iris or corneal malformation. Initial efforts at classiﬁcation were directed toward eponyms and syndrome names, and many of these terms are now widely employed and recognized. The Shaffer–Weiss (1970) disease classiﬁcation divides the developmental glaucomas into primary congenital glaucoma, glaucomas associated with developmental anomalies of the eye or the body, and acquired glaucomas.14,18 Recently, an excellent classiﬁcation system has been described by Hoskins, Shaffer, and Hetherington (1984), which uses clinically identiﬁable anatomical defects of the eye as the basis of classiﬁcation.19,20

Microsurgery and trabeculotomy The classic operation for the treatment of primary congenital glaucoma was Barkan’s goniotomy,2 although there has been increasing use of a newer approach, trabeculotomy ab externo. This procedure was simultaneously and independently described by Burian21,22 and Smith23 in 1960. In March, 1960, without the aid of an operating microscope, the ﬁrst external trabeculotomy was performed by Burian on a young girl with Marfan’s syndrome and glaucoma.21 After 2 years, Allen and Burian published another paper on 2

trabeculotomy ab externo.22 At about the same time (1960) in London, Redmond Smith, an early microsurgeon, developed an operation that he called ‘nylon ﬁlament trabeculotomy.’23 This involved cannulating Schlemm’s canal with a nylon suture at one site, threading the suture circumferentially, withdrawing it at another site, and pulling it tight like a bowstring. The surgical technique of trabeculotomy ab externo is basically a combination of that originally evoked by Burian and Smith and modiﬁed by Harms (1969),24,25 Dannheim (1971)26,27 and McPherson (1973).28–30 Following World War II, the Zeiss Optical Instrument Company relocated to southern Germany near the ancient university town of Tubingen. Seeking to develop new markets and products, Zeiss approached Harms, who told him ideas for an ophthalmic operating microscope. A prototype was produced, and the era of ophthalmic microsurgery began. In 1966 Harms organized the First International Symposium of the Microsurgery Study Group in Tubingen. Among the ophthalmologists in attendance was Samuel D. McPherson, Jr., of Durham, NC. Impressed by the excellent results being claimed for external trabeculotomy, McPherson remained after the symposium to observe Harms in surgery and learn the procedure. McPherson then became the ophthalmologist most associated with the procedure in the United States and its most proliﬁc proponent in the American ophthalmic literature.28–31 Throughout the 1960s, the popularity of external trabeculotomy grew in Europe. By the Second International Symposium of the Microsurgery Study Group in Burgenstock in 1968, the procedure was widely used throughout Europe. When Harms and Allen eventually met, Allen was the ﬁrst to tell Harms of the Iowa City work. Although astonished, Harms thereafter gave Burian and Allen credit for the ﬁrst description of the procedure. The introduction of the microsurgical techniques as exempliﬁed by trabeculotomy revolutionized the prognosis for patients with primary congenital glaucoma, with most studies citing an initial success rate of 80–90%.24,28–37 Trabeculotomy ab externo38–39 and goniotomy40 remain as the preferred initial procedure in the surgical management of primary infantile glaucoma. The need for ‘glaucoma enucleations’ has markedly decreased over the last 50 years, with enucleation for open-angle glaucoma (including congenital glaucoma) now almost fallen into oblivion.41 During the last 50 years, ophthalmological care has improved, various pressure-lowering and antiinflammatory drugs have been developed, new surgical techniques have been introduced, and, probably most importantly, the operating microscope has been incorporated into clinical practice. These advances have enhanced the efﬁcacy of treatment while minimizing complications, which has improved greatly the prognosis for congenital glaucoma.

References 1. Anderson JR. Hydrophthalmia or congenital glaucoma: its causes, treatment, and outlook. Cambridge University Press: London; 1939. 2. Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217–221.

References 3. Barkan O. Goniotomy knife and surgical contact glasses. Arch Ophthalmol 1950; 44:431–433. 4. Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 1948; 32:701. 5. Barkan O. Technic of goniotomy for congenital glaucoma. Arch Ophthalmol 1949; 41:65. 6. Worst JGF. The pathogenesis of congenital glaucoma. Royal Van Gorcum: Assen, Netherlands; 1966. 7. Anderson DR. Pathology of the glaucomas. Br J Opthalmol 1972; 56:146–157. 8. Anderson DR. The pathogenesis of primary congenital glaucoma, presented at Third Meeting of Pan-American Glaucoma Society, Miami, Florida, Feb 29, 1979. 9. Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485. 10. Hansson HA, Jerndal T. Scanning electron microscopic studies of the development of the iridocorneal angle in human eyes. Invest Ophthalmol 1971; 10:252–265. 11. Maul E, Strozzi L, Munoz C, Reys C. The outflow pathway in congenital glaucoma. Am J Ophthalmol 1980; 89:667–673. 12. Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Trans Am Acad Ophthalmol 1958; 56:507–570. 13. Worst JGF. Congenital glaucoma. Remarks on the aspect of chamber angle, ontogenic and pathogenic background and mode of action of goniotomy. Invest Ophthalmol 1968; 7:127–134. 14. Shaffer RN, Weiss DI. Congenital and paediatric glaucomas. CV Mosby: St. Louis; 1970. 15. Kwitko ML. Glaucoma in infants and children. Appleton-Century, Crofts: Philadelphia; 1973. 16. Duke-Elder S. System of ophthalmology, Vol III, pt 2, Congenital deformities. CV Mosby: St. Louis; 1963:548–565. 17. Jerndal T, Hansson HA, Bill A. Goniodygenesis – a new perspective on glaucoma. Scriptor: Copenhagen; 1978. 18. Hoskins HD Jr, Kass M. Becker-Scheffer’s diagnosis and therapy of the glaucomas, 6th edn. CV Mosby: St, Louis; 1989:356. 19. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classiﬁcation of the developmental glaucomas. Arch Ophthalmol 1984; 102:1331–1336. 20. Hoskins HD Jr, Hetherington J Jr, Shaffer RN, Welling AM. Developmental glaucomas: diagnosis and classiﬁcation. Symposium on glaucoma: transactions of the New Orleans Academy of Ophthalmology. CV Mosby: St Louis; 1981:172–190. 21. Burian HM. A case of Marfan’s syndrome with bilateral glaucoma. With a description of a new type of operation for developmental glaucoma (trabeculotomy ab externo). Am J Ophthalmol 1960; 50:1187–1192. 22. Allen L, Burian HM. Trabeculotomy ab externo. A new glaucoma operation. Technique and results of experimental surgery. Am J Ophthalmol 1962; 53:19–26.

23. Smith R. A new technique for opening the canal of Schlemm. Preliminary report. Br J Ophthalmol 1960; 44:370–373. 24. Harms H, Dannehim R. Epicritical consideration of 300 cases of trabeculotomy ab externo. Trans Ophthalmol Soc UK 1969; 89:491–499. 25. Harms H, Dannheim R. Trabeculotomy results and problems. In: Machensen G, ed. Microsurgery in Glaucoma. Second International Symposium of the Ophthalmic Micro-Surgery Study Group. Burgenstock, 1968. Adv Ophthalmol 1970; 22:121–130. 26. Dannheim R. Symposium: microsurgery of the outflow channels. Trabeculotomy. Trans Am Acad Ophthalmol Otolaryngol 1972; 76:375–383. 27. Dannheim R. Synposium: microsyrgery of the outflow channels. Trabeculotomy. Techniques and results. Arch Chili Oftal 1971; 28:149–157. 28. McPherson SD Jr. Results of external trabeculotomy. Am J Ophthalmol 1973; 76:918–920. 29. McPherson SD Jr, McFarland D. External trabeculotomy for developmental glaucoma. Ophthalmology 1980; 87:302–305. 30. McPherson SD Jr, Berry DP. Goniotomy vs external trabeculotomy for developmental glaucoma. Am J Ophthalmol 1983; 95:427–431. 31. McPherson SD, Cline JW, McCurdy D. Recent advances in glaucoma surgery, trabeculotomy, and trabeculectomy. Am Ophthalmol 1977; 9:91–96. 32. Luntz MH. Primary buphthalmos (infantile glaucoma) treated by trabeculotomy ab externo. S Afr Arch Ophthalmol 1974; 2:319–334. 33. Luntz MH, Livingston DG. Trabeculotomy ab externo and trabeculectomy in congenital and adult-onset glaucoma. Am J Ophthalmol 1977; 83:174–179. 34. Quigley HA. Childhood glaucoma: results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–225. 35. Anderson DR. In discussion of Quigley HA: Childhood glaucoma. Ophthalmology 1982; 89:225–226. 36. Hoskins HD Jr, Hetherington J Jr, Shaffer RN, Welling AM. Developmental glaucoma: therapy. Proceedings of the New Orleans Academy of Ophthalmology Glaucoma Symposium. CV Mosby: St. Louis; 1981:191–202. 37. Gregersen E, Kessing SVV. Congenital glaucoma before and after the introduction of microsurgery. Results of ‘macrosurgery’ 1943–1963 and of ‘microsurgery’ (trabeculotomy/ectomy) 1970–1974. Acta Ophthalmol 1977; 55:422–430. 38. Luntz MH. The advantages of trabeculotomy over goniotomy. J Pediatr Ophthalmol Strabismus 1984; 21:150–153. 39. Hoskins HD Jr, Shaffer RN, Hetherington J. Goniotomy vs trabeculotomy. J Pediatr Ophthalmol Strabismus 1984; 21:153–158. 40. Walton DS. Goniotomy. In: Thomas JV, Belcher CD III, Simmons RJ, eds. Glaucoma surgery, Chapter 11. Mosby Year Book: St. Louis; 1992:107–121. 41. Rohrbach JM, Schlote T, Thiel HJ. Wolfgang Stock, his ophthalmopathologic collection and progress in glaucoma treatment in the 2nd half of the 20th century. Klin Monatsbl Augenheilkd 1998; 213:87–92.

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Chapter 2 Terminology and classification of developmental glaucomas Introduction Terminology Classiﬁcation Neurocristopathies Conclusion

Introduction The glaucomas that occur at birth or as a result of improper ocular development have been called by many names indicating a variety of structural changes, etiologic factors, inheritance patterns, prognoses and preferred treatments. The terminology used in the literature to describe these rare diseases is confusing and inconsistent. In infancy, elevated intraocular pressure alters the anterior segment in a way that obscures the structural defects responsible for the glaucoma. Also, terms that have general meanings have been employed to describe speciﬁc syndromes. Familiarity with terminology and classiﬁcation systems used to describe the developmental glaucomas is important for clinicians who encounter these patients.

Terminology Different terms have been used to describe glaucoma in infants and children. These are either general terms, terminology related to the age of onset, or terms related to the presumed cause of the glaucoma.

General terms Buphthalmos (Greek: bous = ox + ophthalmos = eye) is derived from the Greek term for ‘ox-eye’, and refers to the marked enlargement that can occur as a result of any type of glaucoma present in infancy. Hydrophthalmia (Greek: hydor = water + ophthalmos = eye) refers to the high fluid content present with marked enlargement of an eye, which can occur in any type of glaucoma presenting in infancy. Buphthalmos and hydrophthalmia are both descriptive terms that do not imply etiology or appropriate therapy, and these terms should not be used diagnostically.

Terminology relating to age of onset In congenital glaucoma, the glaucoma exists at birth, and usually before birth. Infantile glaucoma occurs from birth

until 3 years of life. Juvenile glaucoma occurs after the age of 3 to teenage years. These terms relate to the age at onset of signs and symptoms of glaucoma and do not imply etiologic factor or inheritance pattern of the glaucoma.

Developmental glaucoma Developmental glaucoma refers to glaucoma associated with developmental anomalies of the eye present at birth. This is a broad term that encompasses most of the glaucomas in infants and children. Primary developmental glaucoma refers to glaucoma resulting from maldevelopment of the aqueous outflow system. Secondary developmental glaucoma indicates glaucoma resulting from damage to the aqueous outflow system due to maldevelopment of some other portion of the eye. Secondary developmental glaucoma may, for example, present as angle closure due to pupillary block in a small eye, an eye with micropherophakia, or an eye with a dislocated lens; or it may present as a forward shift of the lens-iris diaphragm as occurs in persistent hyperplastic primary vitreous or retinopathy of prematurity.

Terminology relating to structural maldevelopment Goniodysgenesis indicates fetal maldevelopment of the iridocorneal angle.1 Trabeculodysgenesis is maldevelopment of the trabecular meshwork, iridodysgenesis is maldevelopment of the iris, and corneodysgenesis is maldevelopment of the cornea. These may present either singly or in some combination. Isolated trabeculodysgenesis is the hallmark of primary developmental glaucoma.

Primary congenital glaucoma Primary congenital glaucoma was described by Shaffer and Weiss2 as follows: The most common hereditary glaucoma of childhood, inherited as an autosomal recessive pattern, with a speciﬁc angle anomaly consisting of absence of angle recess with iris insertion directly into the trabecular surface. There are no other major abnormalities of development. Corneal enlargement, clouding and tears in Descemet’s membrane result from elevated intraocular pressure. In many areas of the world this term is used synonymously with infantile glaucoma to designate this particular syndrome 5

Terminology and classification deﬁned by Shaffer and Weiss. In other areas, however, the term infantile retains its intended meaning, indicating glaucoma occurring at birth.3

Table 2.2 DeLuise–Anderson (1983) classification of congenital and infantile glaucoma

Classiﬁcation

2. Secondary infantile glaucoma

Various classiﬁcations of the developmental glaucomas have been employed. Initial efforts at classiﬁcation were directed toward eponyms and syndrome names, and many of these terms are now widely employed and recognized. The Shaffer– Weiss (1970) disease classiﬁcation divides the developmental glaucomas into primary congenital glaucoma, glaucomas associated with congenital anomalies of the eye or the body, and acquired glaucomas (Table 2.1).2,4 This system uses commonly known syndrome or eponym names for the developmental glaucomas, which can be used for most glaucomas in the pediatric age group. Some patients with developmental glaucomas may be difﬁcult to categorize due to unusual or overlapping features. One type of glaucoma not mentioned in the Shaffer–Weiss classiﬁcation is glaucoma associated with aphakia. DeLuise and Anderson (1983)5 classiﬁed the congenital and infantile glaucomas as primary or secondary infantile glaucomas. The secondary infantile glaucomas were associated with different variables (Table 2.2). This system circumvented the need to differentiate between potentially confusing syndromes that had been grouped on the basis of superﬁcial characteristics.

1. Primary infantile glaucoma (congenital glaucoma, trabeculodysgenesis) A. Associated with mesodermal neural crest dysgenesis 1. Iridocorneotrabeculodysgenesis a. Axenfeld’s anomaly b. Rieger’s anomaly c. Peters anomaly d. Systemic hypoplastic mesodermal dysgenesis (Marfan’s syndrome) e. Systemic hyperplastic mesodermal dysgenesis (Weill– marchesani syndrome) 2. Iridotrabeculodysgenesis (aniridia) B. Associated with phakomatoses and hamartomas 1. Neurofibromatosis (Von Recklinghausen’s disease) 2. Encephalotrigeminal angiomatosis (Sturge–Weber syndrome) 3. Angiomatosis retinae (von Hippel-Lindau syndrome) 4. Oculodermal melanocytosis (Nevus of Ota) C. Associated with metabolic disease 1. Oculocerbrorenal syndrome (Lowe’s syndrome) 2. Homocystinurea D. Associated with inflammatory disease 1. Maternal rubella syndrome (congenital rubella) 2. Herpes simplex iridocyclitis E. Associated with mitotic disease 1. Juvenile xanthogranuloma (nevoxanthoendothelioma)

Table 2.1 Shaffer–Weiss (1970) classification of congenital glaucoma I. Primary congenital glaucoma (primary infantile glaucoma) II. Glaucoma associated with congenital anomalies A. Late developing primary infantile glaucoma (late developing primary congenital glaucoma)

2. Retinoblastoma F. Associated with other congenital disease 1. Trisomy 13-15 syndrome (Patau’s syndrome) 2. Rubinstein–Taybi syndrome 3. Persistent hyperplastic primary vitreous

C. Sturge–Weber syndrome D. Neurofibromatosis E. Marfan’s syndrome F. Pierre Robin syndrome G. Homocystinuria H. Goniodysgenesis (iridocorneal neural crest cell dysgenesis: Axenfeld–Reiger syndrome, Peters anomaly) I. Lowe’s syndrome J. Microcornea K. Microspherophakia L. Rubella M. Chromosomal abnormalities N. Broad thumb syndrome O. Persistent hyperplastic primary vitreous III. Secondary glaucomas in infants A. Retinopathy of prematurity B. Tumors 1. Retinoblastoma 2. Juvenile xanthogranuloma C. Inflammation D. Trauma

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An anatomic classiﬁcation of the developmental glaucomas has been proposed by Hoskins, Shaffer, and Hetherington (1984).6 Clinically identiﬁable anatomical defects of the eye were chosen as the basis for this classiﬁcation because they were readily apparent on examination of the patient (Table 2.3). This system categorizes developmental glaucoma more precisely, but does not apply to glaucomas that occur in the absence of a developmental anomaly of the eye. Certain cases, however, can only be described by anatomical defects. In addition, this classiﬁcation does have prognostic implications. Isolated trabeculodysgenesis, for example, responds more favorably to surgical intervention compared with trabeculodysgenesis associated with iris or corneal anomalies. In the Hoskins–Shaffer–Hetherington system, defects are classiﬁed anatomically according to the three major anterior chamber structures affected: the trabecular meshwork, the iris, and the cornea. Trabeculodysgenesis is deﬁned as maldevelopment of the trabecular meshwork, including the iridotrabecular junction, since the trabecular meshwork is

Classiﬁcation

Table 2.3 Hoskins–Shaffer–Hetherington (1984) classification of the developmental glaucomas I.

Isolated trabeculodysgenesis (malformation of trabecular meshwork in the absence of iris or corneal anomalies) A. Flat iris insertion 1. Anterior insertion 2. Posterior insertion 3. Mixed insertion B. Concave (wrap-around) iris insertion C. Unclassified

II. Iridotrabeculodysgenesis (trabeculodysgenesis with iris anomalies) A. Anterior stromal defects 1. Hypoplasia 2. Hyperplasia B. Anomalous iris vessels 1. Persistence of tunica vasculosa lentis

the trabecular surface, and the surface of the trabecular meshwork may have a stippled, orange peel appearance. The peripheral anterior iris stroma may be thinned, but the corneal stroma and the iris collarette appear normal. In the concave (‘wrap-around’) iris insertion, the plane of iris is well posterior to the normal position of the scleral spur. However, the anterior iris stroma continues upward and over the trabecular meshwork, obscuring the scleral spur and ending just short of Schwalbe’s line. Thus, the iris sweeps around the angle, forming a concave or ‘wrap-around’ insertion. This is most easily recognized in brown irides, and is much less common than flat iris insertion. The trabeculodysgenesis in some eyes cannot be classiﬁed because of corneal clouding or previous surgery. There is no evidence of other iris or corneal malformation in isolated trabeculodysgenesis. The elevated intraocular pressure, however, may cause secondary stretching of these structures.

2. Anomalous superficial vessels C. Structural anomalies

Iridotrabeculodysgenesis

1. Holes 2. Colobomata 3. Aniridia III. Corneoiridotrabeculodysgenesis (malformation meshwork with iris and corneal anomalies)

of

trabecular

A. Peripheral B. Midperipheral C. Central D. Corneal size

formed during separation of the iris from the cornea. Isolated trabeculodysgenesis7 occurs in the absence of developmental anomalies of the iris or cornea. This is the hallmark of primary developmental glaucoma (primary congenital glaucoma) and is the only detectable ocular anomaly in approximately 50% of the infants and juvenile patients with glaucoma.

Trabeculodysgenesis Trabeculodysgenesis occurs in two major forms, distinguished primarily by the appearance of the iridotrabecular junction: flat iris insertion and concave (‘wrap-around’) iris insertion. In the flat iris insertion, patients have an iridotrabecular junction in which the iris appears to insert flatly and abruptly into a thickened trabecular meshwork. The plane of the iris is flat, and the iris tissue stops abruptly where the iris joins the trabeculum. The level of iris insertion may vary along the angle circumference, even posterior to the scleral spur. An anterior insertion, into the trabecular meshwork or anterior to the scleral spur, is the most common type of developmental glaucoma. An anterior insertion usually obscures the view of the ciliary body, although it is possible to see pigmented portion of the anterior ciliary body through a thickened trabecular meshwork when the angle is viewed obliquely from above. Small iris processes may extend onto

In iridotrabeculodysgenesis, malformation of the trabecular meshwork is accompanied by maldevelopment of the iris. Iridodysgenesis or maldevelopment of the iris is subdivided into anterior stromal defects, anomalous iris vessels, and structural anomalies. The anterior stromal defect category includes hypoplasia of the anterior iris stroma, which is the most common iris defect associated with developmental glaucoma. Because the normal infant eye has some peripheral thinning of the iris and because stretching of the iris from pressure can further thin the anterior stroma, diagnosis of true hypoplasia of the anterior stroma should be made only when there is clearly a malformation of the collarette with absence or marked reduction of the crypt layer. The defect, when present, is easily recognized. The sphincter muscle is quite obvious, whereas the iris collarette is either absent or is formed only in the far periphery. Twigs of iris stroma may be seen scattered over the surface of the iris. The iris may insert anteriorly at the level of the scleral spur, and the trabecular meshwork may appear to be thickened. An absent or poorly developed anterior iris stroma has been described as a common ﬁnding in Axenfeld’s anomaly and Rieger’s anomaly.2,8 This defect, when occurring by itself, is typical of familial hypoplasia of the iris with glaucoma.1,9,10 It should not be confused with primary congenital glaucoma since the hypoplastic iris syndrome is dominantly inherited. In hyperplasia of the anterior iris stroma, excessive anterior iris stroma appears as a diffuse thickening of the brown iris covered with abundant small nodules, giving the iris surface a cobblestone appearance. In the series reported by Hoskins et al,6 there were only two cases, both of which were associated with Sturge–Weber syndrome and developmental glaucoma. Vascular anomalies of the iris are divided into those with some form of persistence of the tunica vasculosa lentis, and those with irregularly wandering anomalous superﬁcial vessels. Persistence of tunica vasculosa lentis is characterized by the regular arrangement of the vessels looping into the 7

Terminology and classification pupillary axis either in front of or behind the lens. The normal radial vessels of the iris surface are also prominent because this condition is usually accompanied by hypoplasia of the anterior iris stroma. In anomalous superﬁcial vessels, the vessels wander irregularly over the iris surface, and the pupil is usually distorted. The iris surface has a whorled appearance because of the curving of the radial ﬁbers of the iris. The anterior iris stroma is often hypoplastic. These vascular patterns must be differentiated from exposure of the radial iris vessels that may exist in normal blue-eyed infants or in eyes with hypoplasia of the anterior iris stroma. In such eyes, there is no vascular anomaly even though the vessels are easily seen. Also, the term rubeosis does not apply, because the vessels exist at birth and do not represent neovascularization. Anomalous vessels of the iris are seen most frequently in eyes presenting with glaucoma and cloudy corneas at birth and represent a more severe malformation of the anterior segment. These eyes behave quite differently from eyes whose only structural defect is trabeculodysgenesis. These patients have a poor prognosis for initial surgical treatment and usually require multiple surgeries. The type of iridodysgenesis characterized by structural anomalies or structural iris defects is easily identiﬁed by clinical examination. The anatomic defect may present in several different ways. Holes present as a full thickness opening in the iris without sphincter involvement, as seen in Rieger’s anomaly. Colobomata cause full-thickness defects of the sphincter. In aniridia, most of the iris and all of the sphincter is missing.

Corneoiridotrabeculodysgenesis Although the cornea certainly changes under the influence of elevated intraocular pressure, it may also be the site of a primary malformation. Usually a combination of iris, corneal, and trabecular dysgeneses results in glaucoma. Most commonly there are iridocorneal adhesions, hypoplasia of the anterior iris stroma, and some form of corneal opacity or structural change. For classiﬁcation purposes, corneal defects are grouped according to their location as peripheral lesions, midperipheral lesions, and central lesions. Glaucoma may also be associated with abnormalities of corneal size, including microcornea and macrocornea. Peripheral corneal lesions occur adjacent to and concentric with the limbus and extend no more than 2 mm into clear cornea. Generally, these changes involve the entire circumference of the cornea and are often seen as posterior embryotoxon with adherent iris tissue (e.g., Axenfeld’s anomaly). Midperipheral lesions usually involve a sector of the cornea and are almost always opacities with iris adhesions. The iris is quite dysgenetic, manifested by hypoplasia of the stroma, hole formation, and pupillary abnormalities (e.g., Rieger’s anomaly). Central corneal anomalies are usually opacities, often with central stromal thinning. Hoskins et al (1984)6 reported two cases with a hole through the cornea, draining aqueous. Most central lesions are round, with associated iris adhesions between the collarette and the margin of the opacity, and have a clear zone separating the lesion from 8

the limbus (e.g., Peters anomaly). Occasionally, maldevelopment of the central portion of the cornea causes adhesions between the lens, iris, and cornea with no anterior chamber formation (e.g., anterior chamber cleavage syndrome, anterior staphyloma). This is an extreme form of central iridocorneodysgenesis. Patients with developmental glaucoma may have microcornea or macrocornea. Microcornea may occur as an isolated defect or may be associated with rubella syndrome, persistent hyperplastic primary vitreous (PHPV), Rieger’s anomaly, and nanophthalmos. Because increased intraocular pressure may stretch these glaucomatous eyes, corneal enlargement is not always a developmental defect. It is important to distinguish megalocornea from the corneal stretching that occurs as a part of the glaucomatous process. Megalocornea may occur as a primary defect or in association with other defects such as Axenfeld syndrome. X-linked recessive megalocornea may be associated with glaucoma, which may occur later in life. The prognosis for control of glaucoma in eyes with corneodysgenesis is not as good as in eyes with isolated trabeculodysgenesis.

Advantages of anatomical classiﬁcation Classiﬁcation by syndromes and eponyms is important because it allows a few words to describe a constellation of characteristics that are frequently found together. However, an anatomical classiﬁcation has certain advantages over eponym or syndrome nomenclature when dealing with developmental anomalies. Often the anomalies are varied and do not ﬁt particular syndrome or eponym patterns. Occasionally, a form not previously seen needs to be categorized and treated. Correct classiﬁcation according to eponym or syndrome may require knowledge of factors not yet known about a particular patient, such as future inheritance pattern, response to therapy, or histopathologic examination. The anatomical classiﬁcation is helpful because it does not require knowledge of the histopathologic ﬁndings, time of onset, response to treatment, inheritance pattern, or any other factor. Patients may be classiﬁed according to more than one classiﬁcation system, and the anatomical classiﬁcation has been useful as a supplement to the more traditional nomenclature. The anatomical classiﬁcation improves communication among researchers in this ﬁeld, because it allows greater precision in describing patients and predicting surgical outcome. At the present time, we recognize the excellent surgical prognosis in patients with isolated trabeculodysgenesis. In patients who have additional developmental defects of the anterior segment, the prognosis is worse compared with isolated trabeculodysgenesis. Patients with associated iris anomalies, especially those with anomalous iris vessels, respond poorly to primary surgical intervention and represent either a more severe form of primary congenital glaucoma or perhaps a different development defect altogether. Those with corneal dysgenesis associated with anomalous superﬁcial iris vessels or other iris abnormalities appear to beneﬁt least from primary surgery.

References

Neurocristopathies It has been recognized that neural crest-derived mesenchymal cells make a major contribution to the development of the tissues of the anterior segment. Therefore, one would expect that a group of ocular diseases exists that involves the cornea, iris, and trabecular meshwork, either singly or in combination and often in association with glaucoma. In some patients, these disorders would also be accompanied by abnormalities of non-ocular tissues that are also derived from neural crest cells, including craniofacial abnormalities, dental malformation, middle ear deafness, and malformation of the base of the skull. Clinical syndromes such as Axenfeld– Rieger syndrome, Peters anomaly, Sturge–Weber syndrome, and other phakomatoses can be interpreted based on their neural crest cell derivation. All of these disorders are believed to provide possible clinical evidence either of abnormalities in the migration of neural crest cells or of terminal interference with cellular interactions.11 These diseases and malformations of cells derived from the neural crest have been grouped together under the term neurocristopathies.12

Conclusion Different classiﬁcation systems with varying terminology have been used to lump and split the large number of disorders associated with glaucoma affecting infants and children. Many patients with classical clinical presentation may be described according to traditional eponyms and syndromes. Hoskins and associates have advocated a shift away from eponyms and syndrome names towards an emphasis on descriptive terminology. Noting that the trabecular meshwork, iris, and cornea are the three major structures involved in these conditions, they suggested the terms

‘trabeculodysgenesis,’ ‘iridodysgenesis,’ and ‘corneodysgenesis’ or a combination thereof, as a system of classifying the developmental glaucomas. While there is value in categorizing disorders on the basis of anatomical descriptions and mechanisms, the wide range of manifestations and the limited understanding of disease mechanisms may make it difﬁcult to apply such a system in all cases of developmental glaucomas. However, more precise terminology should be used whenever possible.

References 1. Jerndal T. Dominant goniodysgenesis with late congenital glaucoma. Am J Ophthalmol 1972; 74:28–33. 2. Shaffer RN, Weiss DI. Congenital and paediatric glaucomas. CV Mosby: St. Louis; 1970. 3. Worst JG. Congenital glaucoma: remarks on the aspect of chamber angle, ontogenetic and pathogenetic background and mode of action goniotomy. Invest Ophthalmol 1968; 7:127–134. 4. Hoskins HD Jr, Kass MA. Becker-Shaffer’s diagnosis and therapy of the glaucomas, 6th edn. CV Mosby: St. Louis; 1989:356. 5. DeLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19. 6. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classiﬁcation of the developmental glaucomas. Arch Ophthalmol 1984; 102:1331–1336. 7. Hoskins HD Jr, Hetherington J, Shaffer RN, Welling AM. Developmental glaucoma: diagnosis and classiﬁcation. In: Proceedings of the New Orleans Academy of Ophthalmology Glaucoma Symposium. CV Mosby: St. Louis; 1981:172–190. 8. Hoskins HD, Shaffer RN. Rieger’s syndrome. A form of irido-corneal mesodermal dysgenesis. Pediatr J Ophthalmol 1972; 9:26. 9. Martin JP, Hart CT. Familial glaucoma. Br J Ophthalmol 1974; 58:536–542. 10. Weatherill JR, Hart CT. Familial hypoplasia of the iris stoma associated with glaucoma. Br J Ophthalmol 1969; 53:433–438. 11. Kupfer C, Datilies MB, Kaiser-Kupfer M. Development of the anterior chamber of the eye: embryology and clinical implications. In: Lutjen-Drecoll E, ed. Basic aspects of glaucoma research: international symposium held at the Department of Anatomy, University ErlangenNürnberg, September 17 and 18, 1981. Schattauer: Stuttgart; 1982. 12. Bolande RP. The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 1974; 5:409.

9

Chapter 3 Embryologic basis of developmental glaucomas Introduction Concepts of anterior ocular segment development Normal development of the anterior segment Theories of abnormal development in primary congenital glaucoma Embryologic basis of other angular neurocristopathies Embryologic basis of different iris anomalies Developmental genetics Conclusion

Introduction During embryonic development, the human eye is derived from both ectoderm (surface and neural ectoderm, including neural crest) and paraxial mesoderm. Many structures that were originally believed to have been derived from mesoderm are now considered to be of neural crest origin. A basic understanding of normal development, particularly related to structures of the anterior ocular segment and theories of abnormal development, is helpful preparation for an understanding of developmental glaucomas.

Concepts of anterior ocular segment development In the classic germ-layer theory of development of the human body, there are three layers in the developing embryo: ectoderm, endoderm, and mesoderm. According to this theory, the ectoderm gives rise to surface epithelia and to the nervous system, the endoderm forms the gut, and the mesoderm gives rise to all other structures that are not derived from either the ectoderm or endoderm. Early studies on the development of the eye1–4 depicted the epithelium of the cornea, the retina, and the neural components of the uveal tract as derived from ectoderm, and the remainder of the ocular structures as developed from the mesoderm. Mesenchymal cells are described as a dispersed population of undifferentiated embryonic cells that are stellateshaped and loosely arranged. Although it still may be true that the non-ectodermal portions of the eye stem from the mesenchymal cells, it is now apparent that these cells differ in their embryonic origin. The importance of this realization lies in the fact that a number of congenital anomalies and other pathologic entities, especially disorders of the anterior

ocular segment, can be more thoroughly understood with consideration of the embryonic lineage of the cells involved.5,6 Recent experimental studies, most using animal models, have shown that a major portion, if not all, of the ocular mesenchyme is derived from neural crest cells.7–13 Neural crest cells may be deﬁned as those neuroectodermal cells that proliferate from the crest of the neural folds at about the time the folds fuse to form the neural tube (Fig. 3.1). The neural crest cells that remain attached to the neural tube eventually differentiate into the cerebral and spinal ganglia and the roots of the dorsal nerves. However, many of the neural crest cells migrate away from the neural tube and form secondary mesenchyme, which differentiates into various body structures (Table 3.1).

Normal development of the anterior segment General development The earliest development of the optic vesicle in humans appears as paired outpouchings, one on each side of the developing neural tube in the region that ultimately will form the diencephalon or forebrain.1,3,14,15 As the optic vesicles extend toward the surface ectoderm, the superior and the inferior walls of the neural tube constrict, so that each optic vesicle is connected to the wall of the forebrain by the so-called optic stalk.

E

NT NC

Figure 3.1 Embryonic formation of neural crest cells (NC). These cells are derived from neuroectoderm located at the crest of the neural folds when the folds fuse to form the neural tube (NT). The cells migrate under the ectoderm (E). 11

Embryologic basis of developmental glaucomas

Table 3.1 Contributions of neural crest-derived mesenchyme and mesodermal mesenchyme to human ocular structures A Neural crest cell derivatives 1 Sclera (except caudal portion) 2 Cornea a Endothelium b Keratocytes 3 Uveal tract a b c d

Fibroblasts of choroid Ciliary body muscles Stromal cells of iris Melanocytes

4 Iridocorneal angle a Trabecular meshwork endothelium 5 Vascular system a ? Pericytes B Mesodermal cell derivatives 1 Caudal region of sclera 2 Vascular endothelium, including Schlemm’s canal 3 Extraocular muscles

Induction of the lens is ﬁrst seen as a thickening of the surface ectodermal cells (the lens placode) at about the 3rd week of gestation. As the lens vesicle forms, the optic vesicle is developing into the optic cup (Fig. 3.2). By the 4th week, differential growth and movement of the cells of the optic vesicle cause the temporal and lower walls of the vesicle to

Retina

Optic cup

move inward against the upper and posterior walls. The two laterally growing edges of the cup eventually meet and fuse. This process also involves the optic stalk and results in the formation of embryonic or optic ﬁssure. The lens vesicle separates from the surface ectoderm by the 6th week.3 At this time, the optic cup, which arises from neural ectoderm, has reached the periphery of the lens. A triangular mass of undifferentiated cells overrides the rim of the cup and surrounds the anterior periphery of the lens. From this tissue mass will arise portions of the cornea, iris, and the anterior chamber angle. The undifferentiated cells are derived from cranial neural crest cells origin.7–13 The anterior chamber is formed by three waves of tissue derived from the mass of undifferentiated (neural crest) cells, which grow in between the surface ectoderm and lens (Fig. 3.3). The ﬁrst wave (avascular) differentiates into the primordial corneal endothelium by the 6th to 7th week and subsequently produces Descemet’s membrane. The second wave (vascular) insinuates between the primordia of the cornea and the lens and gives rise to the pupillary membrane and the stroma of the iris (7th week). In the later months, the pigment epithelial layer of the iris develops from neural ectoderm. The third (avascular) wave grows between the corneal endothelium and epithelium to produce keratocytes, which form the stroma of the cornea. 16,17

Development of anterior chamber angle The aqueous outflow structures in the anterior chamber angle appear to arise from the mesenchymal cells of neural crest cell origin. The precise details of this development, however, are not fully understood. At the 22 to 24 mm stage (7th to 8th week), the anterior chamber angle is undifferentiated and is occupied by loosely arranged mesenchymal cells, and the anterior chamber itself is a slit-like opening. Several hypotheses have been advanced in the attempt to explain the formation of anterior chamber angle, including atrophy3 or resorption18 (progressive disappearance of portion of fetal tissue), cleavage19 (separation of two pre-existing

Optic stalk I Epithelium

III II

Lens vesicle Embryonic fissure

Figure 3.2 Formation of the optic cup. After the optic vesicle extends to the lens placode, the lens pit develops and the optic cup is formed at the end of the optic stalk. The lens pit develops into the lens vesicle within the optic cup. The retina is developed from the inner layers of the optic cup. The embryonic fissure of the optic cup and optic stalk is located inferiorly in this sagittal view. (Modified with permission from reference 7.) 12

Lens

Retina Figure 3.3 Ingrowth of neural crest cells. Three successive waves of ingrowth of neural crest cells are associated with differentiation of the anterior chamber. The first wave (I) forms the corneal endothelium. The second wave (II) forms the iris and pupillary membrane. The third wave (III) develops into keratocytes, which form the corneal stroma.

Normal development of the anterior segment tissue layers due to differential growth rate), and rarefaction20 (mechanical distention due to growth of the anterior ocular segment). More recent work, however, suggests that none of these concepts are completely correct. Anderson21 studied 40 normal fetal and infant eyes by light and electron microscopy and found that the anterior surface of the iris at 5 months gestation inserts at the edge of the corneal endothelium, covering the cells that are destined to become trabecular meshwork. This appears to be what Worst22 called the fetal pectinate ligament, separating the corneoscleral meshwork primordium from the anterior chamber angle. The developmental process does not consist of simple cleavage or atrophy, for with either process the uveal tract would simply split away from the corneoscleral shell and the trabecular tissue. The result would be that the ciliary muscle would extend into the perpheral iris and the ciliary processes would be on the posterior surface of the peripheral iris. The trabecular meshwork later becomes exposed to the anterior chamber as the angle recess deepens and moves posteriorly (Fig. 3.4). Anderson noted a posterior repositioning of the anterior uveal structures in progressively older tissue specimens, presumably due to differential growth rates. The repositioning process is not just the sliding of the uveal tract along the inner side of the sclera but there is also repositioning of the various layers within the uveal tract in relation to one another. At birth, the insertion of the iris and ciliary body is near the level of the scleral spur, and usually posterior to it. On gonioscopy of a normal newborn eye, the insertion of the iris into the angle wall will be seen posterior to the scleral spur in most cases, with the anterior extension of the ciliary body seen as a band anterior to the iris insertion. The iris insertion into the angle wall is rather flat, as the angle recess has not yet formed. Continued posterior sliding of the uveal tissue occurs during the ﬁrst 6 to 12 months of life, which is apparent gonioscopically as formation of the angle recess. Thus, the adult angle conﬁguration in which the iris turns slightly posteriorly before inserting into the ciliary body is not normally present at birth but develops in the ﬁrst year of life.

SC

SS

There is some difference of interpretation regarding the innermost layer of the trabecular meshwork primordium as it is uncovered by the posteriorly receding iris. Anderson21 felt that the smooth surface represents the multilayered mesenchymal tissue, which begins to cavitate by the 7th fetal month. Others have suggested, however, that a true endothelial layer covers the meshwork during gestation. Hansson and Jerndal23 studied human fetal eyes by scanning electron microscopy and described a single layer of endothelium, continuous with that of the cornea, extending over the primitive anterior chamber angle and iridopupillary structures, creating a closed cavity at the beginning of the 5th fetal month. Worst22 observed a similar sheet of flat endothelial cells on the pupillary membrane and felt that the disappearance of this layer progresses centrifugally toward the anterior chamber angle. Hansson and Jerndal23 noted that the anterior chamber angle portion of the endothelial layer begins to flatten, with loss of clear-cut borders, by the 7th fetal month. During the ﬁnal weeks of gestation and the ﬁrst weeks after birth, the endothelial layer undergoes fenestration with migration of cells into the underlying uveal meshwork. Van Buskirk24 also observed intact endothelium completely lining the anterior chamber angle by the second gestational trimester in macaque monkey eyes studied by scanning electron microscopy. He noted that fenestration and gradual retraction of this tissue occurs in the 3rd trimester and progresses in a posterior-toanterior direction. As the endothelium of the cornea and anterior chamber angle begins to differentiate, a distinct demarcation line develops at the primordium of Schwalbe’s line.23 It has also been suggested, based on transmission electron microscopy of eyes from premature infants with gestational ages of 24 to 42 weeks, that formation of the trabecular meshwork begins on the anterior chamber side and progresses toward Schlemm’s canal.25 This is thought to be consistent with some cases of primary congenital glaucoma in which the site of obstruction to aqueous outflow appears to be a thickened tissue adjacent to the inner wall of Schlemm’s canal.25,26 Shields combined various observations into a uniﬁed concept of anterior chamber angle development.27 At 5 months

CE

AR I

AR

MS

L

A

3 Months

B

Figure 3.4 Progressive deepening of the anterior chamber angle. A. At 3 months, the angle recess (AR) is anterior to a rudimentary Schlemm’s canal (SC) and scleral spur (SS) have formed. The corneal endothelium (CE) extends into the angle recess. The pigment epithelium and the marginal sinus (MS) of the ectodermal optic cup is posterior to the angle recess. B. At 4 months, the angle recess has deepened and the marginal sinus has moved anteriorly. The angle recess has extended slightly further from the corneal endothelium. Condensed tissue just posterior to Schlemm’s canal is developing scleral spur. The dilator muscle of the iris (I) has reached its root and the lens (L) has continued to develop. (Modified with permission from reference 7.)

4 Months

13

Embryologic basis of developmental glaucomas gestation, a continuous layer of endothelium creates a closed cavity, and the anterior surface of the iris inserts in front of the primordial trabecular meshwork. In the third trimester, the endothelial membrane progressively disappears from the pupillary membrane, iris, and anterior chamber angle, possibly incorporated into the trabecular meshwork. The peripheral uveal tissue begins to slide posteriorly in relation to the anterior chamber angle structures. Development of the trabecular meshwork begins in the inner, posterior aspect of the primordial tissue and progresses toward Schlemm’s canal and Schwalbe’s line. The normal anterior chamber angle is not fully developed until approximately one year of life.

Theories of abnormal development in primary congenital glaucoma Although it is generally agreed that the intraocular pressure elevation in primary congenital glaucoma is due to an abnormal development of the anterior chamber angle that leads to reduced facility of aqueous outflow, there is no universal agreement as to the nature of the developmental alteration. Theories of mechanism parallel the basic concepts regarding the normal development of the anterior chamber angle, most of which are no longer accepted as being entirely correct. The major theories that have been proposed in the past will be reviewed and the current understanding of the developmental abormality of primary congenital glaucoma will be described. Mann (1928)2 proposed that the anterior chamber angle is formed by atrophy of the mesenchyme and arrest of this process results in retention of abnormal tissue that blocks aqueous outflow in primary congenital glaucoma. Allen, Burian, and Braley (1955)19 postulated that incomplete cleavage of mesoderm results in absent angle recess in primary congenital glaucoma, although the cleavage theory for normal development has not been proved. Barkan (1955)18 suggested that incomplete resorption of the mesodermal cells by adjacent tissue led to the formation of a membrane across the anterior chamber angle. This membrane became known as ‘Barkan’s membrane,’ although its existence has not been proved histologically using light as well as electron microscopy.21,23,26,28–31 Maumenee (1958)28 demonstrated abnormal anterior insertion of the ciliary muscle over scleral spur in infantile glaucoma eyes. He noted that the longitudinal and circular ﬁbers of the ciliary muscle inserted into the trabecular meshwork rather than into the scleral spur, and that the root of the iris can insert directly into the trabecular meshwork. He postulated that these changes might compress the scleral spur forward and externally, thus narrowing Schlemm’s canal. Maumenee (1963)31 also noted the absence of Schlemm’s canal in some histopathologic specimens and suggested that this might be a cause of aqueous outflow obstruction in congenital glaucoma, although others feel this may be a secondary change.32 Worst (1966)22 proposed a combined theory, which included elements of the atrophy and resorption concepts, but rejected the cleavage theory. He suggested that incomplete 14

development of the scleral spur leads to a high insertion of the longitudinal portion of the ciliary muscle on the trabeculum. In addition, he felt that a single layer of endothelial cells cover the anterior chamber angle during gestation, and that its abnormal retention in primary congenital glaucoma constitutes ‘Barkan’s membrane.’ Worst claimed that ‘though histopathological proof of this structure is almost completely lacking... this has little influence on the probability that this concept is valid.’33 Smelser and Ozanics (1971)20 explained primary congenital glaucoma as a failure of anterior chamber angle mesoderm to become properly rearranged into the normal trabecular meshwork. Subsequent light and electron microscopic studies favor this theory.25,26,32,34–36 Kupfer and associates (1978)5 suggested that abnormal neural crest cell migration and a defect of terminal induction by embryonic inducers is the cause of several forms of congenital glaucoma.37,38 Anderson (1981)21,39 provided histopathological support for the high insertion of the anterior uvea into the trabecular meshwork, suggesting that this is due to a developmental arrest in the normal migration of the uvea across the meshwork in the third trimester of gestation. He stated that, in eyes with primary congenital glaucoma, the iris and the ciliary body have the appearance of an eye in the seventh or eighth month of gestation rather than one at full term development. The iris and ciliary body have failed to recede posteriorly, and thus the iris insertion and anterior ciliary body overlap the posterior portion of the trabecular meshwork. Anderson believed that, in infantile glaucoma, the thickened trabecular beams have prevented the normal posterior migrations of ciliary body and iris root. Beauchamp and co-workers (1985)40 have postulated that abnormal extracellular matrix and glycoproteins lead to abnormal anterior segment development by interfering with adductors, inductors, receptors and speciﬁc time sequencing. They state that, in primary congenital glaucoma, the defects in morphogenesis and differentiation (capacitation) can be seen as mild, requiring only a minor ‘remodeling’ by, for example, goniotomy to become functional. McMenamin (1991) observed a marked increase in the volume of extracellular matrix during development.41 Tawara and Inomata (1994) found extensive accumulations of basal lamina-like material containing heparan sulfate-type proteoglycans in the thick subcanalicular tissue in trabeculectomy specimens from patients with developmental glaucoma.42 In summary, primary congenital glaucoma appears to result from a developmental abnormality of anterior chamber angle tissue derived from neural crest cells, leading to aqueous outflow obstruction by one or more of several mechanisms. Developmental arrest may lead to an anterior insertion of iris, insertion of the ciliary muscle directly into trabecular meshwork, and only rudimentary development of the scleral spur (Fig. 3.5). The high insertion of the ciliary body and iris into the posterior portion of the trabecular meshwork may compress the trabecular beams, and the extracellular matrix may be abnormal. In addition, there may be primary developmental defects at various levels of the meshwork and, in some cases, of Schlemm’s canal. However, a true

Embryologic basis of different iris anomalies

SC

II

IV

I

III

Figure 3.5 Meridional representation of the anterior chamber angle showing the embryonic configuration. The features include an anterior insertion of the iris (I), a rudimentary scleral spur (II), insertion of the ciliary muscle directly into the trabecular meshwork (III), and undifferentiated trabecular meshwork (IV). These features also may be observed in eyes with primary congenital glaucoma. SC = Schlemm’s canal. (Adapted with permission from reference 7.)

membrane over the meshwork does not appear to be a feature of this disorder.

Embryologic basis of other angular neurocristopathies It has been recognized that neural crest derived mesenchymal cells make a major contribution to the tissues of the anterior ocular segment. Although major developmental events leading to iridocorneal angle formation occur during the third trimester, embryonic insult much earlier in human gestation can induce an abnormal sequence of events leading to anterior segment dysgenesis.43 The neurocristopathies are a group of ocular diseases that involve the cornea, iris and trabecular meshwork (either singly or in combination), often are associated with glaucoma, and are frequently accompanied by abnormalities of nonocular tissue that are also derived from neural crest cells (e.g., craniofacial and dental malformation, middle ear deafness, malformation of the base of the skull).5 These diseases include Axenfeld–Rieger syndrome, Peters anomaly, and Sturge–Weber syndrome or other phakomatoses. Based on clinical and histopathologic observations and the current concepts of normal anterior segment development, a developmental arrest, late in gestation, of certain anterior segment structures derived from neural crest cells, has been postulated as the mechanism of Axenfeld–Rieger syndrome.27,44 This leads to abnormal retention of the primordial endothelial layer on portions of the iris and anterior chamber angle, and alterations in the aqueous outflow structures. The retained endothelium with associated basement membrane is believed to create the iridocorneal strands, while contraction of the tissue layer on the iris leads to the iris changes, which sometimes continue to progress after birth. The developmental arrest also may account for the high insertion of the

anterior uvea into the posterior trabecular meshwork, similar to the alterations seen in primary congenital glaucoma, and result in incomplete maturation of the trabecular meshwork and Schlemm’s canal. Neural crest cells also give rise to most of the mesenchyme related to the forebrain and pituitary gland, bones and cartilages of the upper face, and dental papillae.7,38,45 This could explain the developmental anomalies involving the pituitary gland, the facial bones, and teeth. Other defects, however, such as those of the umbilicus and genitourinary system, are more difﬁcult to associate with a primary defect of cranial neural crest cells. Peters anomaly is characterized by a spectrum of changes in anterior segment structures, including the lens, the cornea, and the anterior chamber angle.46–48 These changes include defects in the posterior stroma of the cornea, Descemet’s membrane, and endothelium, with or without extension of iris tissue strands from the iris collarette to the edge of the corneal leukoma. They may also include a central keratolenticular stalk and cataract. The corneal abnormalities may result from incomplete migration of the neural crestderived mesenchymal cells during early embryogenesis. Incomplete migration of the ﬁrst wave may leave a central defect in endothelium and Descemet’s membrane, which may couple with a stromal defect because of incomplete migration of the second wave. An anterior staphyloma represents a more severe degree of failure of mesenchyme to differentiate properly so that a thin, ectatic, leukoma lined by uveal tissue replaces the cornea. Numerous theories have been devised to account for the raised intraocular pressure in patients with phakomatoses,49–51 including Sturge–Weber syndrome and neuroﬁbromatosis. Several investigators have reported primary defects in the structures of the aqueous outflow pathways in patients with these syndromes. The abnormalities include malformation or absence of Schlemm’s canal, persistence of embryonic tissue in the trabecular meshwork, or incomplete ‘cleavage’ of the iridocorneal angle.52–56 Abnormalities of neural crest cells could explain the pathogenesis of the associated glaucoma in these patients who have no secondary obstruction to aqueous outflow.

Embryologic basis of different iris anomalies At about the 7th week of gestation a vascular wave insinuates between the primordia of the cornea and the lens to form the anterior portion of the vascular tunic of the lens (pupillary membrane), which later becomes the superﬁcial layer of iris stroma. At the same time, the hyaloid artery has grown through the embryonic ﬁssure of the optic stalk and across the vitreous cavity to the posterior aspect of the lens, where it ramiﬁes as the posterior portion of the vascular tunic of the lens. The annular vessel which forms circumferentially around the mouth of the optic cup sends branches posteriorly (between the rim of the optic cup and the equator of the lens) to anastomose with branches of the hyaloid vessel. These 15

Embryologic basis of developmental glaucomas capsulopupillary vessels are the lateral portion of the vascular tunic of the lens. Each of these portions of the vascular tunic of the lens (anterior pupillary membrane, lateral capsulopupillary vessels and the posterior hyaloid system) atrophies in later embryonic development, leaving the lens avascular in postnatal life. Failure of the anterior portion to atrophy produces a persistent pupillary membrane. If the posterior hyaloid system does not involute, persistent hyperplastic primary vitreous may result.57 In aniridia, although other abnormalities of neural crest cells are possible, several mechanisms involving the capsulopupillary vessels have been suggested,57 including absence of the superﬁcial stromal directional membrane, primary failure of optic cup growth, and persistence of capsulopupillary vessels. If the pupillary membrane fails to form primarily, the optic cup will lack a directional membrane, and only a rudimentary iris will develop. Also, as the optic cup grows axially, it carries with it a layer of mesoderm that will become the deep stromal layer of the iris. A primary failure of the optic cup to grow in may result in a rudimentary iris. In addition, persistence of the capsulopupillary vessels extending from the iris to the lens may block the optic cup as it grows axially between the iris stroma and the lens.

Developmental genetics Experimental models for the anterior chamber angle have been developed that demonstrate organization of cellular and extracellular matrix components with a developmental sequence comparable to humans.58 Analysis of human fetal eyes has shown that uveal trabecular endothelial cells can be identiﬁed in early (12 to 22 weeks) development, and increases of extracellular matrix and intertrabecular spaces can be quantitated.41,59 At the same time, understanding of the molecular genetics of primary congenital glaucoma has improved, suggesting several genes that may play a role in the development of the anterior chamber. The majority of patients with primary congenital glaucoma demonstrate mutations in the cytochrome P4501B1 gene (CYP1B1). This gene is expressed in tissues in the anterior chamber angle of the eye, suggesting a role in anterior chamber angle development.60,61 Anterior segment dysgenesis may occur in patients with mutations of chromosome 6 (6p25), implicating the forkhead transcription-factor gene (FOXC1) in development of the anterior chamber angle.62–66 The speciﬁc morphogens involved in the development of the human anterior chamber angle are not known at this time. In an experimental glaucoma model, anterior segment anomalies resembling those in human developmental glaucoma may be modiﬁed by tyrosinase, suggesting a role for this pathway in the development of the anterior chamber angle.67

Conclusion The current knowledge about the development of the structures of the anterior segment has provided a theoretical basis for the developmental abnormality in congenital glaucoma 16

and other anterior segment anomalies. Evidence is mounting that neural crest cells make a prominent contribution to the embryonic derivation of these structures, and this realization may help provide a better explanation for the pathogenesis of the developmental glaucomas. Relatively little is known at present about the factors that induce the embryonic neural crest cells to differentiate into the structures of the anterior segment in the normal eye, and even less is understood about the causes of abnormalities that result in ocular neurocristopathies.

References 1. Duke-Elder S. System of ophthalmology, Vol III. CV Mosby: St. Louis; 1964. 2. Mann I. The development of the human eye. Cambridge University Press: Cambridge; 1928. 3. Mann I. The development of the human eye, 3rd edn. Cambridge University Press: Cambridge; 1964. 4. Streeter GL. Developmental horizons in human embryos. Contrib Embryol 1951; 34:165–196. 5. Kupfer C, Kaiser-Kupfer MI. New hypothesis of developmental anomalies of the anterior chamber associated with glaucoma. Trans Ophthalmol Soc UK 1978; 98: 213–215. 6. Bahn CF, Falls HF, Varley GA et al. Classiﬁcation of corneal endothelial disorders based on neural crest origin. Ophthalmology 1984; 91:558–563. 7. Tripathi BJ, Tripathi RC. Embryology of the anterior segment of the human eye. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:3–38. 8. Johnston MC, Noden DM, Hazelton RD, et al. Origins of avian ocular and periocular tissues. Exp Eye Res 1979; 29:27–43. 9. Le Douarin N. Migration and differentiation of neural crest cells. In: Moscona AA, Monroy A, eds. Current topics in developmental biology, Vol 16. Hunt RK, ed. Neural development, Part II. Academic Press: New York; 1980. 10. Le Lievre C, Le Douarin N. Mesenchymal derivatives in the neural crest: analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol 1975; 34:125–154. 11. Noden DM. An analysis of migratory behavior of avian cephalic neural crest cells. Dev Biol 1975; 42:106–130. 12. Noden DM. The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Dev Biol 1978; 67:296–312. 13. Noden DM. Periocular mesenchyme: neural crest and mesodermal interactions. In: Jakobiec FA, ed. Ocular anatomy, embryology, and teratology. Harper & Row: Hagerstown, MD; 1982. 14. O’Rahilly R. The prenatal development of the human eye. Exp Eye Res 1975; 21:93–112. 15. Ozanics V, Jakobiec FA. Prenatal development of the eye and its adnexa. In: Jakobiec FA, ed. Ocular anatomy, embryology, and teratology. Harper & Row: Hagerstown, MD; 1982. 16. Wulle KG. Electron microscopy of the fetal development of the corneal endothelium and Descemet’s membrane of the human eye. Invest Ophthalmol 1972; 11:897–904. 17. Hay ED. Development of the vertebrate cornea. Int Rev Cytol 1980; 63:263–322. 18. Barkan O. Pathogenesis of congenital glaucoma. Gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955; 40:1–11. 19. Allen L, Burian HM, Braley AE. A new concept of the development of the anterior chamber angle. Its relationship to developmental glaucoma and other structural anomalies. AMA Arch Ophthalmol 1955; 53:783–798. 20. Smelser GK, Ozanics V. The development of the trabecular meshwork in primate eyes. Am J Ophthalmol 1971; 71:366–385. 21. Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485. 22. Worst JGF. The pathogenesis of congenital glaucoma. An embryological and goniosurgical study. Charles C. Thomas: Springﬁeld; 1966. 23 Hansson HA, Jerndal T. Scanning electron microscopic studies on the development of the iridocorneal angle in human eyes. Invest Ophthalmol 1971; 10:252–265. 24. Van Buskirk EM. Clinical implication of iridocorneal angle development. Ophthalmology 1981; 88:361–367. 25. Tawara A, Inomata H. Developmental immaturity of the trabecular meshwork in congenital glaucoma. Am J Ophthalmol 1981; 92:508–525.

References 26. Maul E, Strozzi L, Munoz C, et al. The outflow pathway in congenital glaucoma. Am J Ophthalmol 1980; 89:667–673. 27. Shields MB. Axenfeld–Rieger syndrome. A theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983; 81:736–784. 28. Maumenee AE. The pathogenesis of congenital glaucoma. A new theory. Trans Am Ophthalmol Soc 1958; 56:507–570. 29. Maumenee AE. The pathogenesis of congenital glaucoma; a new theory. Am J Ophthalmol 1959; 47:827–858. 30. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Trans Am Ophthalmol Soc 1962; 60:140–146. 31. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176. 32. Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157. 33. Worst JGF. Congenital glaucoma. Remarks on the aspect of chamber angle, ontogenic and pathogenic background, and mode of action of goniotomy. Invest Ophthalmol 1968; 7:127–134. 34. Sampaolesi R, Argento C. Scanning electron microscopy of the trabecular meshwork in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 1977; 16:302–314. 35. Rodrigues MM, Spaeth GL, Weinreb S. Juvenile glaucoma associated with goniodysgenesis. Am J Ophthalmol 1976; 81:786–796. 36. Tawara A, Inomata H. Developmental immaturity of the trabcular meshwork in juvenile glaucoma. Am J Ophthalmol 1984; 98:82–97. 37. Kupfer C, Ross K. The development of outflow facility in human eyes. Invest Ophthalmol 1971; 10:513–517. 38. Kupfer C, Kaiser-Kupfer MI. Observations on the development of the anterior chamber angle with reference of the pathogenesis of congenital glaucomas. Am J Ophthalmol 1979; 88:424–426. 39. DeLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19. 40. Beauchamp GR, Lubeck D, Knepper PA. Glycoconjugates, cellular differentiation, and congenital glaucoma. J Pediatr Ophthalmol Strabismus 1985; 22:149–155. 41. McMenamin PG. A quantitative study of the prenatal development of the aqueous outflow system in the human eye. Exp Eye Res 1991; 53:507–517. 42. Tawara A, Inomata H. Distribution and characterization of sulfated proteoglycans in the trabecular tissue of goniodysgenetic glaucoma. Am J Ophthalmol 1994; 117:741–755. 43. Cook CS. Experimental models of anterior segment dysgenesis. Ophthalmic Paediatr Genet 1989; 10:33–46. 44. Shields MB. A common pathway for developmental glaucomas. Trans Am Ophthalmol Soc 1987; 85:222–237. 45. Edward WC, Torczynski E. Neural crest cell behaviour and facial anomalies. Pers Ophthalmol 1981; 5:47. 46. Kenyon KR. Mesenchymal dysgenesis in Peter’s anomaly, sclerocornea and congenital endothelial dystrophy. Exp Eye Res 1975; 21:125–142. 47. Schottenstein EM. Peters anomaly. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:887–897.

48. Waring GO, Rodrigues MM, Leibson PR. Anterior chamber cleavage syndrome: a stepladder classiﬁcation. Surv Ophthalmol 1975; 20:3. 49. Cibis GW, Tripathi RC, Tripathi BJ. Glaucoma in Sturge-Weber syndrome. Ophthalmology 1984; 91:1061. 50. Tripathi RC, Tripathi BJ, Cibis GW. Sturge-Weber syndrome. In: Gold DH, Weinglist TA, eds. The eye in systemic disease. Lippincott: Philadelphia; 1987. 51. Weiss JS, Ritch R. Glaucoma in the phakomatoses. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:899–924. 52. Collins ET, Batten RD. Neuroﬁbroma of the eyeball and its appendages. Trans Ophthalmol Soc UK 1905; 25:248. 53. Hoyt CM, Billson F. Buphthalmos in neuroﬁbromatosis: is it an expression of giantism? J Ped Ophthalmol 1977; 14:228–234. 54. Leib WA, Wirth WA, Geeraets WJ. Hydrophthalmos and neuroﬁbromatosis. Conﬁn Neurol 1958; 19:239. 55. Wheeler JM. Plexiform neuroﬁbromatosis involving the choroid, ciliary body and other structures. Am J Ophthalmol 1937; 20:368. 56. Wiener A. A case of neuroﬁbromatosis with buphthalmos. Arch Ophthalmol 1925; 54:481. 57. Laibson PR, Waring GO. Disease of the cornea. In: Harely RD, ed. Paediatric ophthalmology. WB Saunders: Philadelphia; 1975. 58. Smith RS, Zabaleta A, Savinova OV, John SW. The mouse anterior chamber angle and trabecular meshwork develop without cell death. BMC Dev Biol 2001; 1:3. 59. McMenamin PG. Human fetal iridocorneal angle: a light and scanning electron microscopic study. Br J Ophthalmol 1989; 73:871–879. 60. Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye 2000; 14(Pt 3B):422–428. 61. Stoilov I, Jansson I, Sarfarazi M, Schenkman JB. Roles of cytochrome p450 in development. Drug Metabol Drug Interact 2001; 18:33–55. 62. Jordan T, Ebenezer N, Manners R, McGill J, Bhattacharya S. Familial glaucoma iridogoniodysplasia maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly. Am J Hum Genet 1997; 61:882–888. 63. Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/wingedhelix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998; 63:1316–1328. 64. Smith RS, Zabaleta A, Kume T, et al. Haploinsufﬁciency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet 2000; 9:1021–1032. 65. Nishimura DY, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001; 68:364–372. 66. Lehmann OJ, Ebenezer ND, Ekong R, et al. Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions. Invest Ophthalmol Vis Sci 2002; 43:1843–1849. 67. Libby RT, Smith RS, Savinova OV, et al. Modiﬁcation of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 2003; 299:1578–1581.

17

Chapter 4 Epidemiology and genetics of developmental glaucomas Introduction Incidence Heredity Genetic studies Genetic counseling

The majority of patients (about 60%) are diagnosed by age 6 months, and 80% are diagnosed within the ﬁrst year of life. A slight predominance of males is common (about 65%), and involvement is usually bilateral (about 70%). Figure 4.1 shows the demographic data for a group of Indian patients with primary congenital glaucoma. Except for the high rate of consanguinity, the demographic data is typical of primary congenital glaucoma.

Introduction In the pediatric age group, glaucoma is a heterogeneous group of disorders. Primary congenital glaucoma is rare, with an incidence of approximately 1 in 10 000 births in Europe and the United States. Nonetheless, although it is less common compared with primary open-angle glaucoma in adults, primary congenital glaucoma is the most common form of glaucoma in children. The majority of cases of primary congenital glaucoma occur sporadically. Most of these patients demonstrate a recessive pattern with incomplete or variable penetrance and possibly multifactorial inheritance, while some pedigrees suggest an autosomal dominant inheritance. Several genetic loci have been identiﬁed that may play a role in primary congenital glaucoma. Genetics of disorders associated with glaucoma in children have also been evaluated, including Axenfeld–Rieger anomaly and aniridia.

Incidence Primary congenital glaucoma is a rare inherited eye disorder which accounts for 0.01–0.04% of total blindness. The disease is usually manifested at birth or early childhood (before 3 years of age). The incidence of primary congenital glaucoma varies from one population to another. In western developed countries, the incidence is approximately 1 in 10 000 births.1 The incidence of primary congenital glaucoma is increased when founder effect or a high rate of consanguinity is found in a population. The ‘founder effect’ is a gene mutation observed in high frequency in a speciﬁc population due to the presence of that gene mutation in a single ancestor or a small number of ancestors. The incidence is 1 in 1250 in the Slovakian Roms (Gypsies),2 1 in 2500 in the Middle East,3 and 1 in 3300 in Andhra Pradesh, India.4 In the Indian state of Andhra Pradesh, the disease accounts for 4.2% of all childhood blindness.4 The high incidence of the disease observed among the Roms may be due to a founder effect, whereas consanguinity may play an important role in the high incidence observed in the Middle East and India.5–8

Heredity Most cases of primary congenital glaucoma occur sporadically. Patients with a familial pattern usually show a recessive inheritance with incomplete or variable penetrance and possibly multifactorial inheritance. Transmission of disease in successive generations was also reported in several pedigrees, suggesting an autosomal dominant inheritance pattern.9,10 Pseudodominant mode of inheritance may also occur in a few patients with primary congenital glaucoma. These families show parent–child transmission of the disease.5,6,8,11 The disease is familial in 10–40% of cases with variable penetrance (40–100%).1,6,12,13

Genetic studies Loci of recessively inherited primary congenital glaucoma (gene symbol GLC3) have been identiﬁed by genetic linkage analysis (Table 4.1). To date, GLC3A has been mapped to

Sex

Male

Involvement

Bilateral

Heredity

Sporadic

Consanguinity 0%

Female

Yes 20%

No 40% 60% Percentage

80%

100%

Figure 4.1 Demographic data for 129 patients with primary congenital glaucoma from L.V. Prasad Eye Institute in Hyderabad, India. There is a high incidence of consanguinity (47%) in this population. The majority of cases are bilateral (86%) with 14% unilateral, there is a slight majority of males (57%), and most (87%) are sporadic with 13% familial, all of which are typical of primary congenital glaucoma. 19

Epidemiology and genetics

Table 4.1 Known genetic loci for primary congenital glaucoma Locus

Location

Inheritance

Mutated gene (MIM)

Reference

GLC3A

2p21

AR

CYP1B1 (601771)

14

GLC3B

1p36

AR

Unknown

15

AR, autosomal recessive; MIM, Mendelian Inheritance in Man number.

chromosome 2 (2p21)14 and GLC3B to chromosome 1 (1p36).15 The majority of patients with congenital glaucoma map to GLC3A on chromosome 2 (2p21). Families linked to these loci display severe phenotypes with autosomal recessive inheritance pattern. Some types of juvenile onset glaucoma that have an autosomal dominant inheritance pattern have been mapped to chromosome 1q23–q25 (TIGR/MYOC gene). The positional candidate gene approach has shown that mutations in CYP1B1 gene (encoding the cytochrome P450 enzyme) in the GLC3A locus are associated with the primary congenital glaucoma phenotype.5 Mutated gene in GLC3B is yet to be identiﬁed. The predominant genetic cause of this disorder in the Middle East (Turkey and Saudi Arabia) is mutation in CYP1B1 gene. Several mutations from various ethnic backgrounds have been implicated in the pathogenesis of this disorder. To date more than 50 mutations in the coding region of CYP1B1 gene have been identiﬁed.6–8,16–30 It has been reported that 87% of familial and 27% of sporadic cases are due to mutations in this gene.10 Extensive allelic heterogeneity has been noticed in several populations except the Slovakian Roms. Molecular genetic studies in Slovakian Roms revealed that there is locus, allelic, and clinical homogeneity of primary congenital glaucoma in this population. This homogeneity observed was due to the founder effect of a single ancestral mutation E387K, which is found segregating with the disease phenotype in this community.7 Analysis of families from Turkey and Slovakia showed complete penetrance, whereas Saudi Arabian families showed reduced penetrance.10,31 Reduced penetrance was attributed to the possible existence of a dominant modiﬁer locus that is not genetically linked to CYP1B1.18 Only a small proportion of Japanese families (20%) showed mutations in CYP1B1, whereas majority of the families (85%) in Middle East showed mutations in this gene.21 In several families, no mutations were found in the CYP1B1 coding regions or a single heterozygous mutation was found. This could be due to mutations in the promoter or regulatory sequences of the gene, or could be linked to another locus for primary congenital glaucoma.10,32 Digenic inheritance is an inheritance mechanism resulting from the interaction of two non-homologous genes. Digenic inheritance in glaucoma has been shown recently in two instances: in early-onset glaucoma in humans and also in the mouse. CYP1B1 and MYOC mutations were identiﬁed in early-onset glaucoma in humans,33 whereas mutations in CYP1B1 and FOXC1 were detected in the mouse with earlyonset glaucoma.34 This suggests that mutations in genes other than CYP1B1 could cause primary congenital glaucoma. 20

Primary congenital glaucoma is caused by unknown developmental defects in the trabecular meshwork and anterior chamber angle of the eye.10 Because angle structures are mainly derived from the neural crest cells, it is possible that defects in genes expressed in neural crest cells could also contribute to primary congenital glaucoma. Primary congenital glaucoma phenotypes have been associated with CYP1B1 mutations in Indian patients.8 Reddy and coworkers screened 146 primary congenital glaucoma patients from 138 pedigrees and reported six distinct CYP1B1 mutations from 45 primary congenital glaucoma patients from India.25 These include four novel mutations (ins 376 A or Ter@223{frameshift}, P193L, E229K, and R390C) and two known mutations (G61E and R368H). Of the mutations identiﬁed, R368H was the predominant mutation causing primary congenital glaucoma in India. This allele was found in a very low proportion of patients from the Middle East and Brazil, but in India 16.2% of the patients screened had this mutation.25 This indicates that the mutation frequency varies depending on the geographical location as well as ethnic background. Though a spectrum of CYP1B1 mutations from various ethnic backgrounds have been implicated in the pathogenesis of primary congenital glaucoma, very few studies have reported genotype–phenotype correlations. A severity index was developed for primary congenital glaucoma, and the severity of disease was correlated with the genotype.32 All patients with severe phenotypes showed poor prognoses (r = 0.976; P < 0.0001). Of the mutations studied, frameshift and R390C homozygous mutations were associated with very severe phenotypes and very poor prognoses. This approach may help guide therapy and counsel the afflicted family regarding the likelihood of progression of the disorder.

Genetic studies of Axenfeld–Rieger anomaly Axenfeld–Rieger anomaly is a congenital maldevelopment of the anterior segment of the eye that may be associated with glaucoma.35 It is inherited as an autosomal dominant trait, and 50–75% of the patients develop glaucoma.36 The anomaly is actually a spectrum of developmental defects of the anterior chamber of the eye, with wide variability in expression. Ocular features of Axenfeld–Rieger anomaly include prominent anterior Schwalbe’s line, abnormal angle tissue, hypoplastic iris, polycoria, corectopia, and glaucoma.37 The gene for this disorder has been mapped to the chromosome 6p25 region.36 A few mutations in a forkhead/wingedhelix transcription factor gene FOXC1 (formerly known as FREAC3 and FKHL7) have been implicated in the pathogenesis of this disorder.38–41

Genetic studies of aniridia Aniridia is a hereditary anomaly associated with varying degrees of absence of iris tissue, occurring in approximately 1.8 per 100,000 live births. The incidence of glaucoma in aniridia ranges from 6 to 75% in clinical studies.42 In the

References majority (approximately 85%) of patients, aniridia is inherited as an isolated, autosomal dominant trait, with variable expressivity. In the isolated form, aniridia is not associated with other systemic manfestations. In isolated aniridia, two-thirds of the patients have an affected parent (familial), while the remaining one-third of cases are the result of new mutations (sporadic). Wilms’ tumor occurs more frequently in sporadic cases. Approximately 13% of patients have an autosomal dominant form of aniridia that is associated with Wilms’ tumor, genitourinary abnormalities, and mental retardation (WAGR syndrome). Two percent of patients affected with aniridia have an autosomal recessive form that is associated with cerebellar ataxia and mental retardation (Gillespie’s syndrome). Aniridia is frequently the result of a deletion on chromosome 11. The genetic locus for aniridia has been established as the PAX6 gene, which is located on the eleventh chromosome, speciﬁcally on the 11p13 segment.43 Various PAX6 gene mutations have been described to account for aniridia.44–51 Molecular genetic techniques have been used to screen the PAX6 gene for mutations for prenatal diagnosis of aniridia.52 Fluorescence in situ hybridization (FISH) testing has been helpful in identifying patients at risk for Wilms’ tumor.53–55

Genetic counseling Genetic counseling for glaucoma patients usually includes providing information about the risks of glaucoma in children and other close relatives.42 It is the physician’s responsibility to inform patients and their relatives of the risk of developing the disease and the implications of the disease for their health. Also, patients must be informed of the need for early, regular monitoring in potentially affected offspring. Rarely, glaucoma patients in their reproductive years may make reproductive decisions based on information from the physician. As the understanding of the genetic basis of childhood glaucomas improves, and DNA-based diagnostic tests become more widely available, genetic counseling for childhood glaucomas will become more effective. Identiﬁcation of genes and the spectrum of mutations causing primary congenital glaucoma will have both basic and clinical relevance. It may help in early treatment and diagnosis, in carrier detection and genetic counseling, in population screening and prenatal diagnosis, in establishing genotype–phenotype correlations and prognosis, in understanding pathogenesis, and in the development of better treatment strategies. Because of the potentially high life-long morbidity of childhood glaucomas,56 improved understanding of the genetics of these disorders would be expected to have an impact on the quality of life in patients with pediatric glaucomas.

References 1. Francois J. Congenital glaucoma and its inheritance. Ophthalmologica 1972; 181:61–73. 2. Genicek A, Genicekova A, Ferak V. Population genetical aspects of primary congenital glaucoma. I. Incidence, prevalence, gene frequency, and age of onset. Hum Genet 1982; 61:193–197.

3. Jaffar MS. Care of the infantile glaucoma patient. In: Reineck RD, ed. Ophthalmol Annual. Raven Press: New York; 1988:15. 4. Dandona L, Williams JD, Williams BC, Rao GN. Population-based assessment of childhood blindness in Southern India. Arch Ophthalmol 1998; 116:545–546. 5. Stoilov I, Akarsu AN, Sarfarazi M. Identiﬁcation of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet 1997; 6:641–647. 6. Bejjani BA, Lewis RA, Tomey KF, et al. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 1998; 62:325–333. 7. Plasilova M, Stoilov I, Sarfarazi M, et al. Identiﬁcation of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. J Med Genet 1999; 36:290–294. 8. Panicker SG, Reddy ABM, Mandal AK, et al. Identiﬁcation of novel mutations causing familial primary congenital glaucoma in Indian pedigrees. Invest Ophthalmol Vis Sci 2002; 43:1358–1366. 9. Duke-Elder S. Congenital deformities. In: Duke-Elder S, ed. System of Ophthalmology. Mosby: St. Louis; 1969:548–565. 10. Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye 2000; 14:422–428. 11. Stoilov I, Akarsu AN, Alozie I, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1. Am J Hum Genet 1998; 62:573–584. 12. Westerlund E. Clinical and genetic studies on the primary glaucoma diseases. NYT Norsdic Forlag, Arnold Busck: Copenhagen; 1947. 13. Gencik A. Epidemiology and genetics or primary congenital glaucoma in Slovakia: description of a form of primary congenital glaucoma in gypsies with autosomal recessive inheritance and complete penetrance. Dev Ophthalmol 1989; 16:75–115. 14. Sarfarazi M, Akarsu AN, Hossain A. Assignment of a locus (GLC3A) for primary congenital glaucoma (buphthalmos) to 2p21 and evidence for genetic heterogeneity. Genomics 1995; 30:171–177. 15. Akarsu AN, Turacli ME, Aktan SG, et al. A second locus (GLC3B) for primary congenital glaucoma (buphthalmos) maps to the 1p36 region. Hum Mol Genet 1996; 5:1199–1203. 16. Plasilova M, Ferakova E, Kadasi L, et al. Linkage of autosomal recessive primary congenital glaucoma to the GLC3A locus in Roms (Gypsies) from Slovakia. Hum Hered 1998; 48:30–33. 17. Kakiuchi-Matsumoto T, Isashiki Y, et al. A novel truncating mutation of cytochrome P4501B1 (CYP1B1) gene in primary infantile glaucoma. Am J Ophthalmol 1999; 128:370–372. 18. Bejjani BA, Stockton DW, Lewis RA, et al. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modiﬁer locus. Hum Mol Genet 2000; 9:367–374. 19. Martin SN, Sutherland J, Levin AV, et al. Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness. J Med Genet 2000; 37:422–427. 20. Ohtake Y, Kubota R, Tanino T, Miyata H, Mashima Y. Novel compound heterozygous mutations in the cytochrome P450 1B1 (CYP1B1) in a Japanese patient with primary congenital glaucoma. Ophthal Genet 2000; 21:191–193. 21. Mashima Y, Susuki Y, Sergeev Y, et al. Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2001; 42:2211–2216. 22. Kakiuchi-Matsumoto T, Isashiki Y, Ohba N, et al. Cytochrome P4501B1 gene mutations in Japanese patients with primary congenital glaucoma. Am J Ophthalmol 2001; 131:345–350. 23. Michels-Rautenstrauss KG, Mardin CY, Zenker M, et al. Primary congenital glaucoma: three case reports on novel mutations and combinations of mutations in the GLC3A (CYP1B1) gene. J Glaucoma 2001; 10:354–357. 24. Stoilov IR, Costa VP, Vasconcellos JPC, et al. Molecular genetics of primary congenital glaucoma in Brazil. Invest Ophthalmol Vis Sci 2002; 43:1820–1827. 25. Reddy ABM, Panicker SG, Mandal AK, et al. Identiﬁcation of R368H as a predominant CYP1B1 allele causing primary congenital glaucoma in Indian patients. Invest Ophthalmol Vis Sci 2003; 44:4200–4203. 26. Belmouden A, Melki R, Hamdani M, et al. A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco. Clin Genet 2002; 62:334–339. 27. Ohtake Y, Tanino T, Suzuki Y, et al. Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma. Br J Ophthalmol 2003; 87:302–304. 28. Soley GC, Bosse KA, Flikier D, et al. Primary congenital glaucoma. A novel

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single-nucleotide deletion and varying phenotypic expression for the 1546–1555dup mutation in the GLC3A (CYP1B1) gene in 2 families of different ethnic origin. J Glaucoma 2003; 12:27–30. Sitorus R, Ardjo SM, Lorenz B, Preising M. CYP1B1 gene analysis in primary congenital glaucoma in Indonesian and European patients. J Med Genet 2003; 40:e9. Colomb E, Kaplan J, Garchon HJ. Novel cytochrome P450 1B1 (CYP1B1) mutations in patients with primary congenital glaucoma in France. Hum Mutat 2003; 22:496. Sarfarazi M, Stoilov I, Schenkman JB. Genetics and biochemistry of primary congenital glaucoma. Ophthalmic Clin North Am 2003; 16:543–554. Panicker SG, Mandal AK, Reddy ABM, et al. Correlations of genotype with phenotype in Indian patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2004; 45:1149–1156. Vincent LA, Billingsley G, Buys Y, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modiﬁer gene. Am J Hum Genet 2002; 70:448–460. Libby RT, Smith RS, Savinova OV, et al. Modiﬁcation of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 2003; 299:578–581. Shields MB, Buckely E, Klintworth GK, Thresher R. Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 1985; 29:387–409. Gould DB, Mears AJ, Pearce WG, Walter MA. Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25. Am J Hum Genet 1997; 61:765–768. Alward WLM. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 2000; 130:107–115. Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/wingedhelix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998; 63:1316–1328. Nishimura YD, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001; 68:364–372. Panicker SG, Sampath S, Mandal AK, et al. Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly. Invest Ophthalmolol Vis Sci 2002; 43:1358–1366. Komatireddy S, Chakrabarti S, Mandal AK, et al. Mutation spectrum of FOXC1 and clinical genetic heterogeneity of Axenfeld-Rieger anomaly in India. Mol Vis 2003; 9: 43–48.

42. Netland PA, Wiggs JL, Dreyer EB. Inheritance of glaucoma and genetic counseling of glaucoma patients. Int Ophthalmol Clin 1993; 33:101–120. 43. Mintz-Hittner HA. Aniridia. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas. Mosby: St. Louis; 1996:859–874. 44. Jordan T, Hanson I, Zaletayev D, et al. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet 1992; 1:328–332. 45. Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet 1992; 2:232–239. 46. Davis A, Cowell JK. Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet 1993; 2:2093–2097. 47. Axton R, Hanson I, Danes S, et al. The incidence of PAX6 mutation in patients with simple aniridia: an evaluation of mutation detection in 12 cases. J Med Genet 1997; 34:279–286. 48. Azuma N, Hotta Y, Tanaka H, Yamada M. Missense mutations in the PAX6 gene in aniridia. Invest Ophthalmol Vis Sci 1998; 39:2524–2528. 49. Lauderdale JD, Wilensky JS, Oliver ER, Walton DS, Glaser T. 3′ deletions cause aniridia by preventing PAX6 gene expression. Proc Natl Acad Sci USA 2000; 97:13755–13759. 50. Zumkeller W, Orth U, Gal A. Three novel PAX6 mutations in patients with aniridia. Mol Pathol 2003; 56:180–183. 51. Dharmaraj N, Reddy A, Kiran V, et al. PAX6 gene mutations and genotypephenotype correlations in sporadic cases of aniridia from India. Ophthalmic Genet 2003; 24:161–165. 52. Churchill AJ, Hanson IM, Markham AF. Prenatal diagnosis of aniridia. Ophthalmology 2000; 107:1153–1156. 53. Muto R, Yamamori S, Ohashi H, Osawa M. Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am J Med Genet 2002; 108:285–289. 54. Gronskov K, Olsen JH, Sand A, et al. Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identiﬁes 80% of mutations in aniridia. Hum Genet 2001; 109:11–18. 55. Crolla JA, Cawdery JE, Oley CA, et al. A FISH approach to deﬁning the extent and possible signiﬁcance of deletions at the WAGR locus. J Med Genet 1997; 34:207–212. 56. Craig JE, Mackey DA. Glaucoma genetics: where are we? Where will we go? Curr Opn Ophthalmol 1999; 10:126–134.

Chapter 5 Pathology and pathogenesis of developmental glaucomas Introduction Barkan’s membrane theory Histopathological observations in primary congenital glaucoma Histopathological observations in secondary glaucoma Causes of elevated intraocular pressure Effects of elevated intraocular pressure in the infant eye Conclusion

Introduction The initial theory for the pathogenesis of primary congenital glaucoma was Barkan’s membrane theory, which attributed resistance to aqueous flow to an imperforate membrane covering the angle structures. This membrane, however, has not been conﬁrmed histopathologically. Known histopathological changes in primary congenital glaucoma include an anterior iris insertion, thickened trabecular beams, compressed trabecular sheets with loss of intertrabecular spaces, iris processes, and insertion of the ﬁbers of the ciliary muscle into the trabecular meshwork. The main theory that accounts for these changes is a developmental arrest of the anterior chamber angle structures derived from neural crest cells during gestation. The degree of angle immaturity has been correlated with the age of presentation of glaucoma, with more severe angle immaturity or dysgenesis presenting in the perinatal period. Other mechanisms have been proposed for other congenital and secondary glaucomas.

Barkan’s membrane theory The initial observations of Barkan1–7 suggested that in primary infantile glaucoma a thin, imperforate membrane covering the anterior chamber angle of the eyes prevents aqueous humor outflow, and leads to increased intraocular pressure. At the time of goniotomy, the theory asserts, this surface tissue is severed, the peripheral iris ‘falls’ posteriorly, and aqueous humor flow is established.8 This surface membrane, given the eponymic name Barkan’s membrane, was proposed as an endothelial surface that normally breaks apart, but which persists in congenital glaucoma. Indeed, Hansson and Jerndal9 demonstrated in scanning electron micrographs a continuous endothelial surface layer of trabecular meshwork that normally cavitates during the last weeks of fetal

development, but could conceivably remain imperforate in primary infantile glaucoma. Several reasons have been proposed for the lack of histopathological conﬁrmation of a persistent membrane in primary congenital glaucoma, including: inadequacy of the specimens examined,10,11 surgical manipulation of the infant eye before specimens are obtained for histopathological examination, the late stage of the disease (with secondary changes) that is typically available for microscopic study, and artifacts induced by the ﬁxation process itself.9–11 However, even in suitable specimens, Anderson,10,12 Hansson,9 Maul and co-workers,11 and Maumenee13 could ﬁnd no evidence of a membrane in any of the specimens they examined by light and electron microscopy. The most likely explanation for no histopathological conﬁrmation of a persistent membrane is that a membrane has little or no role in the pathogenesis of primary congenital glaucoma.

Histopathological observations in primary congenital glaucoma Based on the numerous examinations of the anterior chamber angle of eyes with primary congenital glaucoma, certain microscopic and ultrastructural observations have been conﬁrmed in this disease (Table 5.1).8,10,11–22 These studies have shown an anterior iris insertion with thickened and compact trabecular beams and excessive extracellular matrix material. Proliferation of ﬁbrous tissue has been described at the inner wall of Schlemm’s canal, with accumulation of collagen ﬁbers and agglomerations of microﬁbrillar material.23 The microﬁbrillar material was found to form basement membrane-like structures and ﬁngerprint-like patterns.23 Figure 5.1 shows the common microscopic ﬁndings in primary congenital glaucoma. An anterior insertion of the iris is a characteristic ﬁnding. The general appearance has been described as nondifferentiation of the trabecular meshwork and persistence of embryonic characteristics. The thickening of the uveal cords may prevent the posterior migration of the ciliary body and iris that normally occurs during the last weeks of gestation, thus causing incomplete differentiation of the angle.10,24,25 Observations strongly suggest developmental immaturity26 of the trabecular meshwork and Schlemm’s canal system, rendering it functionally incompetent. Corneal ﬁndings by in vivo confocal microscopy have been described in patients with primary congenital glaucoma.27 There was a reduction of keratocyte density in the stroma, 23

Pathology and pathogenesis

Table 5.1 Microscopic and ultrastructural observations in primary congenital glaucoma Location

Finding

Iris

Anterior insertion (with open angle configuration)8,10,11–14 Iris processes (also called pectinate ligaments16) present14,17 Longitudinal fibers of ciliary muscle insert directly onto trabecular meshwork, because scleral spur not yet developed10,12,13,18,19,41

Trabecular meshwork

Trabecular beams thicker than normal10,11 Deeper trabecular sheets compressed with decreased intertrabecular spaces9–11

Schlemm’s canal

Amorphous material in the subendothelial region10,11 Few Holmberg15 vacuoles (vesicles) on endothelial surface of Schlemm’s canal, presumably due to decreased flow of aqueous10,11 Some cases reported of faulty development or absence of Schlemm’s canal.20–22 Congenital absence of canal is very rare, if it exists at all. Most often, canal is compressed and difficult to identify

Ciliary processes

Anteriorly displaced and pulled inward due to enlarging globe with non-enlarging lens10,13,18,19,41

Membrane

Instead of imperforate membrane, proposed by Barkan1–7 and Worst,8 most observers have documented compact mass of compressed trabecular tissue, giving the illusion of a continuous membrane.10,11,14

C

AC TM I

Figure 5.1 Microscopic appearance of the anterior chamber angle in a patient with primary congenital glaucoma. There is an anterior insertion of the iris (I), which extends over the poorly developed trabecular meshwork (TM). Schlemm’s canal is present adjacent to the trabecular meshwork. The ciliary muscle and the rudimentary scleral spur insert into the trabecular meshwork. C = cornea, AC = anterior chamber. Periodic acidSchiff (PAS) stain, original magniﬁcation ×100. Original photograph provided courtesy of William R. Morris, MD.

and discontinuous hyperreflective structures overhanging the endothelial layer at the level of Descemet’s membrane. The endothelium showed severe polymegethism, pleomorphism, and a markedly decreased cell density, with focal cellular lesions.27

Histopathological observations in secondary glaucoma Cases of secondary glaucoma associated with other neonatal or developmental anomalies include anterior chamber cleavage syndrome of Axenfeld and Rieger and Peters anomaly 24

(iridocorneotrabeculodysgenesis), encephalotrigeminal angiomatosis (Sturge–Weber syndrome), neuroﬁbromatosis (Von Recklinghausen disease), maternal rubella syndrome, and retinopathy of prematurity. The pathogenesis in most of these disorders is different from that in primary infantile glaucoma, as evidenced by the poor response of these secondary glaucomas to classic infantile glaucoma surgery, such as goniotomy or trabeculotomy ab externo. The occasional association of trabecular dysgenesis with other anomalies may be explained by a common neural crest cell origin of the affected tissue.28 Although Axenfeld–Rieger syndrome is characterized by a prominent, anteriorly displaced line of Schwalbe with attachment of tissue strands of peripheral iris, several reports have documented structural alterations in the trabecular meshwork and Schlemm’s canal29–31 similar to that seen in primary congenital glaucoma. Shields has postulated that the changes in the anterior segment of the eyes in patients with Axenfeld–Rieger syndrome result from an arrest in the development of the tissues derived from neural crest cells that occurs late in gestation.29,30 Peters anomaly is characterized by a spectrum of changes in the anterior segment structures. Only a few studies have been reported on the structure of the trabecular meshwork and Schlemm’s canal in patients with Peters anomaly. In one patient who had total peripheral anterior synechia, Schlemm’s canal and the trabecular meshwork could not be identiﬁed.32 Kupfer et al33 studied the trabeculectomy specimen from the eye of a 2-year-old child with Peters anomaly and reported that the trabecular beams showed thickening, with the presence of ‘curly’ collagen. The endothelial cells contained an abnormal amount of phagocytosed pigment granules. Again, the authors suggested that the structural alterations could have resulted from a failure of differentiation of neural crest-derived cells that were destined to form the trabecular and corneal endothelial cells.33,34 In some cases of Sturge–Weber syndrome, the anterior chamber angle is histologically identical to that in primary

Conclusion infantile glaucoma. Phelps35 and Weiss36 have suggested that elevated episcleral venous pressure may be an additional problem in the etiology of the glaucoma in this condition. Trabeculectomy specimens from patients with Sturge–Weber syndrome revealed not only a compact trabecular meshwork with thickening and hyalinization of the trabeculae, but also the presence of amorphous material and abnormal collagen. The juxtacanalicular region showed an excess of extracellular elements (granuloamorphous material, basal lamina material, banded and non-banded structures), and degenerative changes were noted in the cellular component.37 These alterations in patients with Sturge–Weber syndrome suggested premature aging of the trabecular meshwork and Schlemm’s canal. The defect in the aqueous outflow pathway can arise early in the development of the anterior chamber, because some of these patients have glaucoma and even buphthalmos soon after birth. In the maternal rubella syndrome, the anterior chamber angle resembles that in primary infantile glaucoma both clinically and histopathologically.12 Indeed, several cases of reported primary infantile glaucoma were actually cases of maternal rubella syndrome, which were either inapparent or subclinical.12 Retinopathy of prematurity has been associated with a shallow anterior chamber and angle-closure glaucoma.38 However, gonioscopic observation in infants with stage IV and V retinopathy of prematurity has identiﬁed structural abnormalities of the anterior chamber angle that may have developmental origin.39

Causes of elevated intraocular pressure Clinical evidence supports the theory that the obstruction to aqueous flow with a resultant increase in intraocular pressure is located at the trabecular meshwork area. Incision into the trabecular meshwork by goniotomy or trabeculotomy relieves the obstruction and normalizes the intraocular pressure in the majority of cases. The surgical incision may relieve the compaction of the trabecular sheets and allow the trabecular spaces to open. Surgical success with goniotomy is achieved by a superﬁcial incision into the trabecular meshwork.40 The iris root drops backward as the blade incises the meshwork. It may be that the thickened cords of uveal meshwork hold the iris anteriorly. Superﬁcial incision of the thickened uveal meshwork will allow the iris root to drop posteriorly with accompanying posterior rotation of the scleral spur. This might allow opening of the corneoscleral trabecular sheets with improved outflow of aqueous. Schlemm’s canal has been found to be open both histologically and clinically, and does not appear to be the site of obstruction to aqueous flow.10,41 Tissue abnormalities adjacent to or involving the internal wall of Schlemm’s canal are a less likely source for the resistance to aqueous flow as it is unlikely that goniotomy incisions consistently cut this tissue. Incisions at various heights along the meshwork have all been found to relieve the resistance to outflow.42

Effects of elevated intraocular pressure in the infant eye During the ﬁrst 3 years of life, the extracellular ﬁbers of the eye are softer and more elastic than in older individuals. Thus, elevation of the intraocular pressure causes rapid enlargement of the globe, which is especially apparent as a progressive corneal and limbal enlargement. The normal neonatal horizontal corneal diameter of 10.0 to 10.5 mm may be enlarged to as much as 16 to 18 mm. As the cornea and limbus enlarge, Descemet’s membrane and the corneal endothelium are stretched. This can result in linear ruptures (Haab’s striae), which in turn can lead to corneal scarring if the problem is chronic. The thinned endothelium may also decompensate in adult life, despite a normal intraocular pressure, when aging changes are superimposed upon the initial endothelial damage.43 As the eye enlarges, the iris is stretched and the overlying stroma may appear thinned. The scleral ring through which the optic nerve passes also enlarges with elevated intraocular pressure, which can lead to an enlargement of the optic cup even in the absence of loss of optic nerve ﬁbers.44 The disc is cupped more quickly in the infant as compared to the adult eye, and reversal of the enlargement can also occur rapidly after normalization of the intraocular pressure. This is probably related to the increased elasticity of the connective tissues of the optic nerve head in the infant eye, which allows an elastic or compression response to fluctuation in intraocular pressure.45,46 Eyes with advanced disease are enlarged in all dimensions. The root of iris and trabecular meshwork are degenerated and thinned, and Schlemm’s canal may not be evident. The ciliary body is atrophic, as are the retina and choroid. The zonules may be degenerated and the lens displaced.43 The optic nerve may show complete cupping.

Conclusion There are certain similarities in the morphologic features of the trabecular meshwork and Schlemm’s canal in most of the disorders associated with the developmental glaucoma. This disorder usually manifests itself as an anterior iris insertion with thickening of the trabecular beams caused by increased amounts of extracellular components, a consequent reduction of the intertrabecular spaces, and an attenuation of the endothelium. These ﬁndings have been described as nondifferentiation of the trabecular meshwork or as persistence of embryonic characteristics. Observations strongly suggest developmental immaturity of the trabecular meshwork and Schlemm’s canal system, which renders it functionally incompetent. The more extensive the immaturity, the earlier the glaucoma appears.

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26

25. Hoskins HD Jr, Hetherington J Jr, Shaffer RN, Welling AM. Development glaucomas: diagnosis and classiﬁcation. In: Symposium on glaucoma. Trans New Orleans Acad Ophthalmol. St. Louis, 1981. 26. Tawara A, Inomata H. Developmental immaturity of the trabecular meshwork in congenital glaucoma. Am J Ophthalmol 1981; 92:508–525. 27. Mastropasqua L, Carpineto P, Ciancaglini M, Nubile M, Doronzo E. In vivo confocal microscopy in primary congenital glaucoma with megalocornea. J Glaucoma 2002;11:83–89. 28. Kupfer C, Kaiser-Kupfer MI. Observations on the development of the anterior chamber angle with reference to the pathogenesis of congenital glaucomas. Am J Ophthalmol 1979; 88(3 Pt 1):424–426. 29. Shields MB. Axenfeld-Rieger syndrome: a theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983; 81:736–784. 30. Shields MB, Buckley E, Eleintworth G, Threshwer R. Axenfeld-Rieger syndrome: a spectrum of developmental disorders. Surv Ophthalmol 1985; 29:387–409. 31. Wolter JR, Somdall GS, Fraliek FB. Mesodermal dysgenesis of anterior eye with a partially separated posterior embryotoxon. J Pediatr Ophthalmol 1967; 4:41. 32. Scheie HG, Yanoff M. Peter’s anomaly and total posterior coloboma of retinal pigment epithelium and choroid. Arch Ophthalmol 1972; 87:525–530. 33. Kupfer C, Kuwabara T, Stark W. The histopathology of Peters anomaly. Am J Ophthalmol 1975; 80:653. 34. Kupfer C, Kaiser-Kupfer MI. New hypothesis of developmental anomalies of the anterior chamber associated with glaucoma. Trans Ophthalmol Soc UK 1978; 98:213. 35. Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Trans Ophthalmol Soc UK 1978; 98:213. 36. Weiss DI. Dual origin of glaucoma in encephalotrigeminal haemangiomatosis. Trans Ophthalmol Soc UK 1973; 93:477–493. 37. Cibis GW, Tripathi RC, Tripathi BJ. Glaucoma in Sturge-Weber syndrome. Ophthalmology 1984; 91:1061–1071. 38. Pollard ZF. Secondary angle-closure glaucoma in cicatricial retrolental ﬁbroplasia. Am J Ophthalmol 1980; 89:651–653. 39. Hartnett ME, Gilbert MM, Richardson TM, et al. Anterior segment evaluation of infants with retinopathy of prematurity. Ophthalmology 1990; 97:122–130. 40. Shaffer RN, Weiss DI. Congenital and pediatric glaucomas. CV Mosby: St. Louis; 1970. 41. Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Am J Ophthalmol 1959; 47:827–858. 42. Hoskins HD Jr, Kass MA. Becker-Shaffer’s diagnosis and therapy of the glaucomas. CV Mosby: St. Louis; 1989. 43. Spencer WH. Ophthalmic pathology, an atlas and textbook. WB Saunders: Philadelphia; 1985. 44. Quigley H. Childhood glaucoma, results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–226. 45. Quigley HA. The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 1977; 84:358–370. 46. Wu SC, Huang SC, Kuo CL, Lin KK, Lin SM. Reversal of optic disc cupping after trabeculectomy in primary congenital glaucoma. Can J Ophthalmol 2002; 37:337–341.

Chapter 6 Primary congenital glaucoma Introduction Clinical features The diagnostic examination Conditions with overlapping signs of epiphora and ‘red-eye’ Conditions with overlapping signs of corneal enlargement Conditions with overlapping signs of corneal edema and opacity Conditions with overlapping signs of optic nerve abnormalities Conditions associated with increased intraocular pressure Conclusion

Introduction Primary congenital glaucoma refers to a speciﬁc form of developmental glaucoma, which has an isolated maldevelopment of the trabecular meshwork (isolated trabeculodysgenesis) not associated with other developmental ocular anomalies or ocular disease that can raise the intraocular pressure. The term primary infantile glaucoma has the same meaning as primary congenital glaucoma. It is the most common form of developmental glaucoma, occurring in about 1 in 10 000 live births. Primary congenital glaucoma is typically bilateral, although a signiﬁcant intraocular pressure elevation may

occur in only one eye in 25 to 30% of the cases. In this chapter, we will discuss the clinical features, the diagnostic examination and the differential diagnosis of the disease.

Clinical features Primary congenital glaucoma may present with a classic triad of symptoms (Fig. 6.1A-C).1 These symptoms include epiphora (excessive tearing), photophobia (hypersensitivity to light), and blepharospasm (squeezing of the eyelids). Any combination of these symptoms should arouse suspicion of glaucoma in an infant or child. These symptoms are secondary to the corneal irritation that accompanies corneal epithelial edema caused by elevated intraocular pressure. Epiphora may at ﬁrst be attributed to a non-patent tear drainage system, which is a common condition. Photophobia commonly occurs and may be of gradual or sudden onset. The parents may ﬁrst notice that their baby keeps the eyes closed when exposed to sunlight, and their usual reaction is to provide some shade, in the belief that the baby is merely showing normal sensitivity to light. Moderate photophobia may be noticed indoors as well; the baby will often keep the eyes closed even while eating. Severe photophobia will cause the baby to keep the eyes closed constantly or to hide the face from bright lighting or even from ordinary lighting. During the period of apparent discomfort, the baby may also be seen to rub the eyes frequently.2 Primary infantile glaucoma may also present as a ‘red eye,’ mimicking conjunctivitis and delaying the correct diagnosis.1,3,4 Enlargement of the eye occurs under the influence

A B

Figure 6.1 Symptoms of primary congenital glaucoma include: tearing (A), photophobia (B), and blepharospasm (C).

C

27

Primary congenital glaucoma of the elevated intraocular pressure, with the major enlargement occurring at the corneoscleral junction. A hazy appearance of the cornea can be intermittent in the early stages and precede breaks in Descemet’s membrane.

Ocular enlargement Ocular enlargement occurs because the neonatal globe is still distensible (Fig. 6.2). The corneal and scleral collagen have not hardened sufﬁciently to prevent their expansion with increased intraocular pressure. This change includes stretching in all parts of the infant eye, including the cornea, the anterior chamber angle, the sclera, the optic nerve, the scleral canal, and the lamina cribrosa.1,3 The normal neonatal horizontal corneal diameter is approximately 10 to 10.5 mm, increasing an additional 0.5 to 1.0 mm in the ﬁrst year of life.5 Enlargement of the corneal diameter to greater than 12 mm in the ﬁrst year of life is highly suspicious of developmental glaucoma.1 This enlargement is more obvious in asymmetric cases. Corneal enlargement from increased intraocular pressure predominantly occurs before the age of three years,6,7 but the sclera may be deformable until approximately age 10 years.8 The increased intraocular pressure stretches the corneal endothelium and Descemet’s membrane, resulting in breaks in these layers, ﬁrst described by Haab in 1863 (Fig. 6.3).4,7 As the edge of the rupture in Descemet’s membrane contracts into scrolls and ridges,7 inﬁltration of the aqueous humor causes localized corneal edema, compounding any diffuse edema that may also be present simply because of the elevated intraocular pressure. Haab’s striae form as endothelial cells lay down new basement membrane (Descemet’s membrane) and hyaline ridges develop.4,7 Haab’s striae are typically horizontal and linear when they occur centrally in the cornea, but parallel or curvilinear to the limbus when they occur peripherally.4,6,7,9 They do not seem to occur in corneas smaller than 12.5 mm in diameter. Breaks in the Descemet’s membrane from increased intraocular pressure rarely occur after the age of three years.7 Haab’s striae occur in approximately 25% of patients who have primary infantile

Figure 6.2 Infant with megalocornea and corneal edema due to primary congenital glaucoma. 28

A

B Figure 6.3 Slit lamp biomicroscopy of Haab’s striae with diffuse illumination (A) and retroillumination (B).

glaucoma at birth and are evident in over 60% of infants presenting with primary infantile glaucoma at 6 months of age.10,11 The initial corneal edema in primary infantile glaucoma is simple epithelial edema due to elevated intraocular pressure. In chronic primary infantile glaucoma, there is permanent stromal edema.14,15 Persistence and progression of primary infantile glaucoma may lead to permanent sequelae, such as stromal scarring, chronic stromal corneal edema, and irregular corneal astigmatism12,13 Younger children are more likely to present to the ophthalmologist with corneal edema and haze, while older children will more commonly present with frank corneal enlargement or buphthalmos.16 The sclera also expands slowly under the influence of elevated intraocular pressure. The associated scleral thinning causes an increased visibility of the underlying uveal tissue in the neonate and a ‘blue-sclera’ appearance (Fig. 6.4). With the gradual deposition of additional extracellular connective tissue that occurs during growth,17 no further expansion of sclera occurs. Once buphthalmos has developed, the globe usually does not return to normal size with normalization

Clinical features

A

B Figure 6.4 Child with congenital glaucoma and ‘blue-sclera’ appearance due to buphthalmos and scleral thinning.

Figure 6.5 Glaucomatous optic nerve damage in congenital glaucoma with elevated intraocular pressure. Note the enlarged optic nerve cup with an intact neural rim (A). End-stage cupping (B).

of the intraocular pressure.17 As the axial length of the globe increases, myopia and astigmatism result.18,19 Myopic astigmatism and anisometropia are particularly common in cases of unilateral or asymmetric primary infantile glaucoma.

Optic nerve cupping The optic nerve changes in primary congenital glaucoma are different from those occurring in adults with glaucoma. Optic nerve cupping may occur rapidly and early in infants (Fig. 6.5).17,20–23 Also, cupping of the optic nerve head may be reversible with normalization of intraocular pressure (Fig. 6.6),24,25 whereas this is uncommon in the adult with glaucomatous induced optic nerve head damage.17 Several hypotheses have been proposed to explain the optic nerve head cupping in infants. First, it has been suggested that astroglial cell loss may be induced by elevated intraocular pressure.21 Second, extracellular fluid shifts in the optic nerve head may contribute to changes in the cup at different levels of intraocular pressure.26 Third, posterior displacement of the lamina cribrosa and enlargement of the scleral canal may account for changes in the cup size with fluctuation of intraocular pressure during infancy.17,27 The third explanation

Figure 6.6 Appearance of the optic nerve of a child with congenital glaucoma after surgical treatment and normalization of the intraocular pressure. The cup shows mild concentric enlargement with increased vertical cup-to-disc ratio and an intact neural rim.

currently seems most reasonable, based on the fact that the connective tissue of the lamina cribrosa is not yet mature during early neonatal life.17 Reversibility of cupping in infantile glaucoma appears to be due to incomplete development of connective tissue in the lamina cribrosa, which allows posterior movement of the 29

Primary congenital glaucoma optic disc tissue in response to elevated intraocular pressure, with an elastic return to normal when the pressure is lowered.17 In those cases in which the damage to a neonatal optic nerve head is not partially or completely reversible upon normalization of intraocular pressure, either a portion of the stretching is permanent with remolding of the connective tissue, or there has been a loss of glia and axons.17 If the intraocular pressure is not controlled, tearing, photophobia, and blepharospasm may worsen. Continued enlargement of the cornea with more tears of Descemet’s membrane may lead to corneal scarring, erosion, and ulcerations. Stretching and rupture of the zonules can cause lens subluxation. Blunt trauma in these enlarged eyes can lead to hyphemas, retinal detachment, and rupture of the globe, and phthisis bulbi may be the ﬁnal outcome.

A

The diagnostic examination The history of blepharospasm, photophobia, and tearing is very useful in arousing the suspicion of glaucoma and in distinguishing it from other conditions. Other historical information of importance is the family history of glaucoma, associated congenital defects, maternal history of infection (rubella) during pregnancy, and birth history.13

Initial examination During the initial ofﬁce visit, the examiner may be able to observe the degree of photophobia, blepherospasm, and tearing. Ideally, the examiner captures the infant’s open-eyed attention with a slowly blinking flashlight or a gentle jingle of keys and then can observe the corneal size and clarity without touching the baby’s face. The effort may be unavoidably impossible, and often the inexperienced examiner aggravates the difﬁculty by moving too quickly or frightening the child with a loud clatter of keys, whistling and clicking sounds, and perhaps a futile effort to pry open the lids. Meanwhile, the anxious mother, realizing the importance of the examination and sensing the examiner’s desire for a close look, frantically pats and rocks the baby. As the baby cries, the mother and the examiner not only feel frustrated in their efforts, but become tense. The examiner with insight will avoid making the examination more difﬁcult than it is already. At this point, the examiner may have determined that there is an enlarged or cloudy cornea, and that the patient has photophobia, blepharospasm, and tearing. The diagnosis of primary infantile glaucoma may be sufﬁciently obvious or likely that it is almost certain that examination and possible surgery under general anesthesia is going to be required. In any event, it should be kept in mind that the goal of the ofﬁce examination is to accomplish an examination sufﬁcient to rule out glaucoma making examination under anesthesia unnecessary; or to gather enough information to establish the suspicion of primary infantile glaucoma, justifying administration of general anesthesia for a more complete ocular examination and probable surgery. Usually, a complete ocular examination, including slit-lamp examination, applanation tonometry, gonioscopy, and optic 30

B Figure 6.7 Distracting an awake child with a bottle or pacifier can permit accurate measurement of intraocular pressure and a thorough examination. Many children are cooperative with an office examination (A, B). In these photographs, the intraocular pressure is measured using an electronic (Tonopen) tonometer.

nerve evaluations can be performed in the ofﬁce in children over the age of 5 years and, with some training, in children as young as 3 years. Timing the examination of an infant to occur when the child is placated by a bottle feeding can be helpful in allowing a complete examination (Fig. 6.7). If necessary, in an older child, a mild sedative such as chloral hydrate syrup (25 to 50 mg/kg body weight) can be given (Fig. 6.8). Chloral hydrate can mildly lower the intraocular pressure, and this approach is usually not necessary if patience and gentleness are exercised. Visual ﬁeld examination can be performed at 5 to 6 years of age, but the patient’s short attention span and poor ﬁxation often prevent a detailed study. The older and more cooperative the child, the more detailed the examination. By the age of 8 to 10 years, most children can cooperate for a full quantitative visual ﬁeld examination.

Figure 6.8 A mild sedative such as chloral hydrate can allow complete examination, and avoid deep anesthesia (examination under anesthesia) requiring respiratory support. This child’s anterior segment and anterior chamber angle is examined using Koeppe gonioscopy.

The diagnostic examination A reasonably good ofﬁce examination can sometimes be performed in infants younger than 3 months of age using the infant diagnostic lens of Richardson–Shaffer or a small diameter Koeppe lens. The lens assists in examination of the anterior segment, and enables the physician to perform gonioscopy and visualize the optic disc. It is well tolerated when placed on the eye with topical anesthesia, and, with a direct ophthalmoscope set at approximately +10.0 diopters, a very good view of the posterior pole can be obtained even with small pupils and mild corneal haze.

Examination under anesthesia (EUA) The examination under anesthesia, when necessary, provides an opportunity to thoroughly examine the eye. Anesthesia should be administered in the operating room by skilled individuals who have experience with pediatric patients. For a brief examination, oftentimes administration of intravenous and mask anesthesia is sufﬁcient. For more prolonged examination and treatment, an endotracheal tube may be necessary. The basic equipment required to perform an adequate examination under anesthesia to ascertain the diagnosis of primary infantile glaucoma is shown in Table 6.1.

Corneal clarity and corneal diameter The cornea is examined to document the presence or absence of corneal edema, breaks in Descemet’s membrane (Haab’s striae), and corneal enlargement in order to distinguish the glaucomatous signs from other corneal abnormalities. The corneal diameter is measured along the horizontal and vertical meridian. The vertical meridian may be difﬁcult to measure accurately due to encroachment of sclera at the superior limbus. Corneal diameter can be measured with calipers, but a problem with calipers is that it may be difﬁcult to judge the actual diameter when the examiner is measuring meridian length. Kiskis and coworkers28 introduced a series of transparent plastic plates (templates) with holes of different diameters in quarter-millimeter increments to ﬁt close to the eye so that the location of the limbus can accurately be

aligned. A corneal diameter greater than 12 mm in the ﬁrst year of life is highly suggestive of infantile glaucoma.1 With an increase in the horizontal diameter above 13 mm, the limbus becomes indistinct, making measurement difﬁcult. However, the measurement should be recorded accurately, even when it is clearly abnormal, to serve as a baseline to allow determination of further corneal enlargement at later examinations.

Refraction Determination of refractive error, including the astigmatic change by streak retinoscopy, is used as a diagnostic method to recognize ocular enlargement and distortion. Assessment of the refractive error also establishes a baseline which can be helpful to judge future progression.

Intraocular pressure measurement Tonometry can be performed with a Schiotz tonometer, Perkins hand-held applanation tonometer, or electronic (Tonopen) tonometer (Fig. 6.9). One method is usually sufﬁcient, although, in cases where uncertainty exists, checks can be performed with other instruments. All anesthetics alter the intraocular pressure of patients with primary infantile glaucoma,29 seemingly in relation to the level of anesthesia29 and as a direct function of their effect on cardiovascular tone.13 A rapid lowering occurs particularly with halothane (Fluothane) anesthesia,13,24,29 which may produce readings 15 to 20 mm below the ‘true’ measurement.29 The intraocular pressure may be at least transiently elevated by cyclopropane or succinylcholine.13 Anesthetic drugs that achieve only light anesthesia and those that induce deeper anesthesia only slowly, such as diethyl ether, cyclopropane,13 or ketamine, allow the intraocular pressure to be measured somewhere between the artiﬁcially elevated intraocular pressure of ‘excitement’ stage of anesthesia and the artiﬁcially

Table 6.1 Equipment for examination under anesthesia (EUA) 1. Pediatric lid speculum 2. Balanced salt solution 3. Tonometer (Perkins and/or Tonopen) 4. Direct ophthalmoscope 5. Retinoscope 6. Koeppe goniolens and light source 7. Calipers or templates with different sized holes (to measure corneal diameter) *8. Portable hand-held slit-lamp *9. Ultrasound (A- or B-mode; ultrasound biomicroscope, [UBM]) *10. Hand-held Kowa camera or a specially adapted fundus camera (for optic disc and possibly fundus photographs) *Optional

Figure 6.9 An examination under anesthesia (administered by mask). The intraocular pressure is measured using the Perkins hand-held applanation tonometer. 31

Primary congenital glaucoma lowered intraocular pressure of deep anesthesia observed with halothane. Standardization of anesthesia for intraocular pressure measurement for diagnosis and follow-up of primary infantile glaucoma is obviously highly desirable, and inconsistent readings should always be interpreted with consideration of the patient’s general state of anesthesia and the speciﬁc anesthetic used.13 The normal intraocular pressure in an infant under halothane anesthesia is said to be approximately 9 to 10 mmHg30 and a pressure of 20 mmHg or more should arouse suspicion.30 The most reliable method of measuring the intraocular pressure is probably with the child awake, if cooperation permits, and the Perkins tonometer has been found to be particularly suitable in this situation.31 In one study, the mean intraocular pressure in unanesthetized newborns was 11.4 ± 2.4 mmHg.32 Another potential source of error is the method of tonometry itself. Schiotz tonometry, a commonly used method for measurement of the intraocular pressure in the operating room, is affected by corneal edema and swelling, corneal surface distortion and irregularities, and by changes in corneal curvature and ocular rigidity, conditions that all exist in primary infantile glaucoma.33,34 In cases of scarred or edematous corneas, the Mackay–Marg tonometer is considered to be more accurate.35–37 The electronic (Tonopen) tonometer is useful, but the mires observed using the Perkins applanation tonometer may be helpful in assessing the accuracy of the measurement. The normal intraocular pressure in an infant is slightly lower than in an adult, but 21 mmHg remains a useful upper limit. There is no one way of measuring intraocular pressure that is ideal. Our preference is the hand-held Perkins applanation tonometer used at that earliest stage of inhalation anesthesia before intubation to reduce errors related to anesthesia, relying on the rest of the examination to interpret the importance of the intraocular pressure reading.

Slit lamp examination This portion of the examination is best performed with a portable hand-held slit lamp. The corneal ﬁndings are judged with magniﬁcation and stereopsis. The anterior chamber in primary congenital glaucoma is characteristically deep, especially when distention of the globe is present. The iris is typically normal, although it may have stromal hypoplasia with loss of the crypts.

Gonioscopy Evaluation of the anterior chamber angle is essential for the accurate diagnosis of the developmental glaucomas. The Koeppe 14 to 16 mm lens with a Barkan light and hand-held binocular microscope provides the surgeon with the appropriate view of the angle (Fig. 6.10). Alternatively, the handheld slit lamp, if available, may be used to visualize the angle through the Koeppe lens. The Goldmann lens may also be used for viewing the angle through the operating microscope. If corneal clouding is marked, the view may be improved 32

Figure 6.10 The Koeppe lens is useful for assessing the anterior segment and the anterior chamber angle, especially during an examination under anesthesia. An excellent view of the disc and macula, also, may be obtained using the Koeppe lens and a direct ophthalmoscope.

by instilling topical glycerine solution or, if necessary, by removing the epithelium with a surgical blade38 or applying a 70% alcohol solution with a cotton applicator. The anterior chamber angle in childhood differs signiﬁcantly from that of adults. In the normal newborn eye, the iris usually inserts posterior to the scleral spur. The anterior extension of the ciliary body is seen as a distinct band anterior to the iris insertion. The iris insertion into the angle is flat, because the angle recess has not yet formed. The trabecular meshwork appears thicker and more translucent than that of the adult. Absence of acquired pigmentation of the trabecular meshwork is normal in the infant eye. Illuminating the angle from the side with a slit beam may help determine the location of the trabecular meshwork posterior to the area where the light beam narrows at the end of the cornea. The formation of the angle recess, characteristic of the adult angle, in which the iris turns slightly posteriorly before inserting into the ciliary body, develops in the ﬁrst 6 to 12 months of life. The normal infant eye may have some thinning of the peripheral iris.2 Gonioscopy of the eye with primary congenital glaucoma reveals an anterior insertion of the iris directly into the trabecular meshwork (Fig. 6.11).39,40 This iris insertion is most commonly flat, although a concave insertion may also be seen. In a concave insertion, the plane of the iris is posterior to the level of the scleral spur, but the anterior stroma of the iris sweeps upward to insert into the trabecular meshwork. The level of the iris insertion may vary at different areas of the angle, with some portions of the iris inserting anterior and other areas posterior to the scleral spur. The surface of the trabecular meshwork may have a stippled appearance and the meshwork may appear thicker than normal. There is no pigmented band present, but a thin section of the ciliary body may be visible through the thickened trabeculum. The peripheral iris may show a thinning of the anterior stroma.

The diagnostic examination

Figure 6.11 Gonioscopic appearance of the anterior chamber angle in an infant with primary congenital glaucoma. Note the high insertion of the iris. There is no definite visible scleral spur.

Although the angle is usually avascular, loops of vessels from the major arterial circle may be seen above the iris, which has been called the ‘Loch Ness Monster phenomenon.’41 In addition, the peripheral iris may be covered by a ﬁne, fluffy tissue that has been referred to as ‘Lister’s morning mist.’41 Sometimes exposure of the radial iris vessels may exist in normal blue-eyed infants or in the eyes with hypoplasia of the anterior iris stroma. In such eyes there is no vascular anomaly even though the vessels are easily seen.42

Ophthalmoscopy Evaluation of the optic disc is an essential part of the examination. Ophthalmoscopy under general anesthesia is most easily performed through a semi-dilated pupil (Fig. 6.12). Mydriasis can be obtained by using a drop of 2.5% phenyl-

ephrine and 1% cyclopentolate. This seldom influences intraocular pressure or systemic blood pressure.43 If surgery is contemplated, ophthalmoscopy should be done without dilatation. One can use the hand-held direct ophthalmoscope to obtain monocular clues of optic nerve head cupping or enlargement. A good view can be facilitated by the use of a Koeppe contact lens, which neutralizes irregular corneal reflexes and also improves the view of the optic disc through a small pupil. The optic nerve head in normal newborns is typically pink, but may have slight pallor, and a small physiological cup is usually present.44 In most cases, the physiologic cupping is bilaterally symmetric, and asymmetry is suggestive evidence of glaucoma. Cup-to-disc ratios greater than 0.3 are rare in normal infants but common in infants with glaucoma and must be considered suspicious. Cupping of the optic nerve is an early sign of increased pressure. Optic nerve cupping occurs much more quickly and at lower pressures than in adults. The infant glaucomatous cup usually has a conﬁguration different from adult glaucomas. Although it can be oval, it is more commonly round, steep walled, and central, surrounded by a uniform pink rim. The cup tends to enlarge circumferentially with glaucomatous progression, which probably results from a stretching of the scleral canal. A decrease in cupping can occur within hours or days after intraocular pressure control in the very young. This is especially marked in infants below 1 year of age.17,29 If therapy is successful, the cup will either remain stable or decrease in size. Evidence of increased cup size is indicative of uncontrolled glaucoma in an individual of any age. To provide records for future comparison, it is best to make a careful drawing or to take photographs of the optic nerve head. Robin and associates19 examined in detail the features of the optic nerve head in their 59 patients with primary infantile glaucoma by stereophotographs when possible and by careful drawings. They found that the average vertical cup/disc ratio was 0.68 ± 0.24 and the average horizontal cup/disc ratio was 0.65 ± 0.24.19 In addition, they found that 14 (25%) of involved eyes had loss of neuroretinal rim tissue at the superior and inferior poles, as in adult glaucomatous optic nerve heads, and 12 (21%) had slit defects in the arcuate area of the nerve ﬁber layer. Finally, they documented three prognostic factors regarding cupping. First, males tended to lose more of the neuroretinal rim tissue compared with females. Second, eyes of bilaterally involved primary infantile glaucoma patients had larger cups than unilaterally glaucomatous patients. Third, the older the patient at the time of the initial diagnosis, the greater the cupping (P < 0.001).19

Ocular fundus photography

Figure 6.12 Examination of the disc is an essential part of the examination under anesthesia. This is also the best opportunity for photographic documentation of the appearance of the optic nerve.

Ocular fundus photography is very useful in keeping a record of the appearance of the optic disc. This is best done when the infant is anesthetized, using a hand-held Kowa camera or a fundus camera placed vertically to obtain fundus pictures. Sometimes it is necessary to put a special contact lens on the eye to see through the small pupil, such as a Koeppe lens without a dimple, or use a Kowa hand-held camera and an indirect lens. 33

Primary congenital glaucoma

Ultrasonography Ultrasonic ocular biometry has been recommended by some investigators for routine use in the diagnosis and follow-up of congenital glaucoma.45,46–48 A-scan measurements can determine axial length, depth of anterior chamber, and lens thickness. The normal axial length in an infant ranges from 17.5 to 20 mm and increases to 22 mm in length by 1 year of age. Several studies have indicated that ultrasonic measurement of the axial length of the eye in infants and children is a highly valuable parameter in the diagnosis of congenital glaucoma. Results conﬁrmed the clinical value of ultrasonic biometry for both the diagnosis of congenital glaucoma in cases with borderline intraocular pressures and to detect glaucoma in the fellow eye of patients with presumed unilateral disease.44,45 Also, the method was effective in the follow-up45–48 of patients with congenital glaucoma who had undergone surgery. It has been reported that the axial length may decrease up to 0.8 mm following surgical reduction of the intraocular pressure.48 The values of the measurements of the anterior chamber depth, the length of the vitreous body, and the axial length are signiﬁcantly higher in glaucomatous eyes. An interesting ﬁnding is that the lens thickness of glaucomatous eyes is notably reduced.46 This is an important contributing factor in the emmetropization of the glaucomatous eye, the axial length of which, when considered as an isolated factor, would predict a higher myopia than observed in glaucomatous eyes.46 In congenital glaucoma, although myopia is a common ﬁnding, its magnitude does not usually reach the expected value based on the enlargement of the eyeball. The ﬁnal refraction will also be influenced by other changes induced by the disease in other eye structures. The enlargement of the eye and the cornea is associated with flattening of the cornea, which reduces myopia. Also, the lens decreases in thickness, probably due to expansion of the scleral ring adjacent to the ciliary body and stretching of the zonular ﬁbers thereby decreasing the lens thickness. Furthermore, the deepening of the anterior chamber due to posterior positioning of the lens as the eye and cornea enlarge can influence the refraction in eyes with congenital glaucoma. All of these factors contribute to the so-called emmetropization, which involves harmonization of the different and interdependent parameters that have an influence on ocular refraction. B-scan ultrasonography can support A-scan measurements in buphthalmic eyes by depicting a generalized enlargement of the globe. When the media are opaque (corneal edema, cataract), B-scan examination can delineate structural abnormalities such as retinal or choroidal detachment, or unsuspected mass lesion. High frequency ultrasound examination of the anterior segment (ultrasonic biomicroscopy or UBM) uses higher resolution imaging to depict the cornea, anterior chamber, iris and angle. UBM has been used to determine angle development values for various post-conceptual age and birth weights, including those of premature infants.49,50 In eyes with trabeculodysgenesis, elongated and anteriorly placed 34

ciliary processes may be noted.51 In congenital glaucoma patients with dense corneal opacities, this technique may be useful in delineating the extent of anterior segment abnormalities to aid in surgical planning.51

Interpretation of examination findings In most cases, after completion of the examination under anesthesia, the ﬁndings of corneal enlargement, optic nerve head changes, and buphthalmos are so typical of primary congenital glaucoma that there is little doubt about the diagnosis and the need for surgery. If the intraocular pressure is normal and the other ﬁndings are present, one can assume the intraocular pressure is artifactually lowered under anesthesia, and still secure the diagnosis and proceed with surgery. If ocular enlargement and optic nerve cupping are not typical or are absent, then it is appropriate to postpone diagnosis and therapy for 3 to 4 weeks, repeating the examination under anesthesia at that time to see if any changes have occurred to allow a clinical diagnosis. It is important to inform the parents of the possibility of a diagnosis of primary infantile glaucoma before the examination under anesthesia and obtain consent for a possible surgical procedure. If the diagnosis is conﬁrmed, goniotomy or trabeculotomy (or combined trabeculotomy–trabeculectomy) can be performed immediately. This spares the patient another inhalation anesthesia, and allows the clinician to proceed with the deﬁnitive procedure for the disease as early as possible.

Differential diagnosis Some of the clinical features of primary congenital glaucoma are also found in other conditions, and these must be considered in the differential diagnosis. Several clinical entities deserve mention, to differentiate them from primary infantile glaucoma. Most have one of the signs or symptoms of primary infantile glaucoma, but none are completely characterized by photophobia, tearing, blepharospasm, and generalized ocular enlargement (buphthalmos) with optic nerve cupping.33 A differential diagnosis for congenital glaucoma is provided in Table 6.2.

Conditions with overlapping signs of epiphora and ‘red-eye’ The most common cause of epiphora in the infant is obstruction of the nasolacrimal drainage system. Photophobia is not associated with this problem and other signs typical of congenital glaucoma are absent. The epiphora of nasolacrimal duct obstruction is distinguished from that of infantile onset glaucoma in that the former condition is usually associated with fullness of the lacrimal sac and often has chronic mucopurulent discharge. Any of several causes of conjunctivitis1,3,4 in the infant can present with redness and tearing. Chemical conjunctivitis secondary to silver nitrate prophylaxis is a common cause in

Conditions with overlapping signs of corneal edema and opacity

Table 6.2 Differential diagnosis of primary congenital glaucoma Conditions with overlapping signs of epiphoria and ‘red eye’ Nasolacrimal duct obstruction Conjunctivitis Corneal epithelial defect, abrasion Meesman’s corneal dystrophy Reis–Buckler’s corneal dystrophy Ocular inflammation (e.g., keratitis, iridocyclitis) Conditions with overlapping signs of corneal enlargement Axial myopia Megalocornea Conditions with overlapping signs of corneal edema or opacity Sclerocornea Tears in Descemet’s membrane (e.g., obstetric trauma) Ulcers (e.g., congenital neonatal corneal herpes infection, congenital syphilis) Metabolic diseases (e.g., oculocerebrorenal syndrome of Lowe, mucopolysaccharidoses, cystinosis, mucolipidoses, amyloidosis, Fabry’s disease, glucose-6-phosphatase deficiency) Peters anomaly Endothelial dystrophies (e.g. posterior polymorphous dystrophy, congenital heriditary endothelial dystrophy) Congenital hereditary stromal dystrophy Dermoid (central corneal dermoid) Conditions with overlapping signs of optic nerve abnormalities Congenital malformation of the disc (e.g., pits, colobomas, hypoplasia) Tilted disc Large physiologic cups Conditions with overlapping signs of increased intraocular pressure Maternal rubella syndrome Secondary infantile glaucoma due to anterior chamber cleavage syndromes, phakomatoses (e.g., Sturge–Weber syndrome, Von Recklinghausen’s disease, Von Hippel–Lindau syndrome, nevus of Ota), and other secondary glaucomas Modified from Raab.33

the newborn. Bacterial, chlamydial, and viral infections are usually associated with a mucoid or mucopurulent discharge and must be ruled out. Corneal epithelial defects or abrasions are frequent causes of acute ocular irritation in children and are diagnosed by history and external examinations. Meesman’s corneal dystrophy usually presents in the ﬁrst several months of life with ocular irritation. Examination reveals multiple clear to gray-white, punctate opacities of the corneal epithelium, which are intra-epithelial cysts. The condition is bilateral, dominantly inherited, and is the probable equivalent of Stocker–Holt dystrophy. Reis–Buckler dystrophy can present in the ﬁrst few years of life with ocular pain secondary to recurrent epithelial erosion. Examination reveals irregular patches of opacity in the region of Bowman’s layer, with progression to a diffuse reticular pattern associated with an anterior stromal haze. Congenital hereditary endothelial dystrophy can also present with tearing and photophobia along with corneal edema. Inflammatory disease, such as keratitis and iridocyclitis, can cause corneal edema and clouding associated with pain, redness and watering. Rubella keratitis may occur in newborn patients.

Conditions with overlapping signs of corneal enlargement High degrees of axial myopia can present with large eyes, including large corneas. The other symptoms and signs of glaucoma are not present. The posterior pole ﬁndings serve to distinguish this condition from primary congenital glaucoma. A tilted appearance of the optic nerve head, peripapillary scleral halo (‘myopic crescent’), and choroidal mottling are characteristic of axial myopia, and are rarely seen in primary congenital glaucoma. Megalocornea1,5 is a condition of marked corneal enlargement, often to diameters of 14.0 to 16.0 mm. Other signs of congenital glaucoma, such as elevated intraocular pressure, abnormal cupping of the optic disc nerve head, or tears in Descemet’s membrane, are not present. These eyes have deep anterior chambers and may have iridodonesis secondary to stretched zonules and a loose lens. On gonioscopic examination, one may ﬁnd a normal angle, prominent iris processes, or a broad dense area of pigmented trabecular meshwork.24 The inheritance appears to be sex-linked, with ninety percent of cases occurring in males. Families have been reported in which some members have megalocornea and others have primary infantile glaucoma.19,52 Indeed, some have considered megalocornea a forme fruste of primary infantile glaucoma.49 These patients, while not in need of treatment, must be followed carefully for possible intraocular pressure changes indicative of primary infantile glaucoma.4,5,52

Conditions with overlapping signs of corneal edema and opacity In sclerocornea, opaque scleral tissue extends into the cornea. Vessels usually accompany the tissue in this typically bilateral (90%), non-hereditary disease. Obstetric trauma can cause rupture of the Descemet’s membrane with resultant corneal edema and clouding. The tears in Descemet’s membrane may mimic the Haab’s striae of primary infantile glaucoma.7 There is no unequivocal way of determining whether breaks in the Descemet’s membrane are due to birth trauma or increased intraocular pressure. It has often been stated that Descemet’s membrane breaks from birth trauma are vertically oriented while those caused by increased intraocular pressure are horizontal.7,53 However, they are also frequently curvilinear and often can run diagonally across the cornea as well. Obstetric corneal trauma is usually unilateral and more commonly affects the left eye because of the higher incidence of left occiput anterior presentation of the infant’s head at birth. There are attendant signs of periorbital skin changes as a result of trauma (bruising), normal intraocular pressure, and no corneal enlargement.7 Congenital or neonatal ocular herpes infections are extremely rare. Ocular herpes in the newborn include one or all of the following: conjunctivitis, epithelial keratitis, epithelial ulcer, stromal immune reaction, cataracts, and necrotizing chorioretinitis.54,55 In congenital ocular herpes, the infection may be acquired in utero via the transplacental route. Neonatal ocular herpes is almost invariably secondary to direct 35

Primary congenital glaucoma exposure to HSV-2 in the birth canal during the late prenatal period or during passage of the baby through an infected canal at birth itself. Corneal involvement in congenital syphilis may manifest as bilateral interstitial keratitis and ulceration. Several metabolic diseases can produce corneal clouding mimicking the corneal edema of primary congenital glaucoma. Other disorders may be associated with glaucoma, although they can be distinguished from primary congenital glaucoma. For example, oculocerebrorenal syndrome of Lowe, an X-linked recessive condition of renal tubular acidosis and cataracts, may be associated with glaucoma.3,4 However, other stigmata of the disease, especially cataracts and nephropathy, differentiate Lowe syndrome from primary congenital glaucoma.3 Mucopolysaccharidoses (MPS) are inborn errors of metabolism characterized by excessive storage of mucopolysaccharides and defective degradation due to deﬁciencies of lysosomal acid hydrolases. In these diseases, excessive keratan sulfate appear in the cornea. In MPS I-H (Hurler syndrome), corneal clouding is a prominent feature of the disease (Fig. 6.13), which helps to differentiate it from Hunter’s syndrome. The opacities are located ﬁrst in the anterior stroma and consist of ﬁne gray punctate opacities. Later the posterior stroma and endothelium become involved. Histologically, ballooned macrophages are found in the cornea. MPS I-S (Scheie syndrome) is a variant of Hurler syndrome. The corneal haze that is often present at birth is very slowly progressive. The cornea appears thickened and somewhat edematous. The cloudiness is more marked in the corneal periphery. MPS II (Hunter syndrome) has clinical and biochemical features similar to those of Hurler syndrome, except Hunter syndrome is less severe. Corneal clouding is generally considered to be absent in Hunter syndrome, although exceptions in some older patients have been recorded. Corneal cloudiness does not occur in MPS III (Sanﬁlippo syndrome); however, corneal clouding is observed in MPS IV (Morquio syndrome). Corneal opacities occur in MPS VI (Maroteax–Lamy syndrome), but slit-lamp examination may be necessary to see them. Corneal clouding is absent or mild in MPS VII (Sly syndrome), which is due to β-glucuronidase deﬁciency. Cystinosis (Lignae–Fanconi syndrome) is a rare autosomal recessive genetic disorder of cystine storage. The lysosomal cystine transport system is defective. In some cases, cystine crystals may be deposited in the cornea and conjunctiva as the only manifestation of cystinosis. However, in the nephropathic type, patients may also develop renal failure and a ‘salt and pepper’ retinopathy. In the cornea, the crystals are glistening, polychromatic, needlelike to rectangular, and distributed throughout the anterior stroma with a slight predilection for the periphery. They appear early as 6 months of age and can cause intense photophobia. Crystals may be found throughout the entire thickness of the cornea,56 if they are extensive, and visual acuity may be reduced. Intracellular crystals have been demonstrated within corneal stromal cells as well as in cells of the iris, ciliary body, choroid, and retinal pigment epithelium. 36

A

B Figure 6.13 Hurler syndrome (MPS I-H). This condition is a mucopolysaccharidosis that may be associated with corneal clouding (A), which may lead to initial consideration of the diagnosis of congenital glaucoma. The habitus of the same patient with MPS I-H (B).

The mucolipidoses are inherited metabolic diseases caused by defects in glycoprotein oligosaccharide degradation or biosynthesis that result in abnormal accumulation of acid mucopolysaccharides, sphingolipids and glycolipids. Progressive corneal clouding is due to accumulation of abnormal storage material around stromal keratocytes. Other ophthalmic manifestations include retinal pigmentary degeneration, a cherry-red spot, and optic atrophy. Psychomotor retardation and other systemic abnormalities are associated with this group of diseases. Amyloid is an eosinophilic material that has an afﬁnity for dyes such as Congo red. Amyloid can be deposited in various tissues of the body, including the eyes, as part of a localized or systemic disease. A specialized form of amyloid deposition in the cornea is seen in lattice corneal dystrophy. Amyloid may be deposited in the cornea as the result of chronic inflammation. The corneas in amyloidosis may show corneal scarring and opaciﬁcation. Familial amyloidosis of the cornea has also been described.

Conditions with overlapping signs of optic nerve abnormalities Sphingolipidoses are caused by a deﬁciency of lysosomal enzymes required for the metabolism of sphingolipids, including gangliosides, cerebrosides, and sphingomyelin. In these disorders, sphingolipids accumulate in lysozymes of cells, which can be identiﬁed by electron microscopy as multimembranous inclusion bodies (zebra bodies). Corneal clouding may occur in Fabry disease and metachromatic leukodystrophy. Fabry disease is an X-linked recessive sphingolipidosis caused by a lack of alpha-galactosidase, which results in accumulation of ceramide trihexoside. The most typical ocular feature is a ﬁne, whorl-like superﬁcial corneal opacity (cornea verticillata). It resembles the corneal opacities found after administration of chloroquine and amiodarone. Corneal opacities have been seen as early as 6 months of age and are presumably caused by the accumulation of sphingolipids in the corneal epithelium. Visual acuity is generally unaffected. Metachromatic leukodystrophy is an autosomal recessive disorder caused by a defect of acylsulfatase A, leading to accumulation of cerebroside sulfate. Corneal clouding may be observed and, unlike Fabry disease, macular grayness or a cherry-red spot and optic atrophy may be observed. In glucose-6-phosphatase deﬁciency (Von Gierke disease), the cornea may show a faint brown peripheral clouding. In general, metabolic disorders with corneal clouding or opacity are associated with normal intraocular pressure and no corneal enlargement, which clinically differentiates them from primary congenital glaucoma. In addition to metabolic disorders, corneal dystrophies may be associated with corneal clouding at an early age. Congenital hereditary stromal dystrophy is an autosomal dominant disease that appears at birth as a bilateral, symmetrical, non-progressive clouding of the central superﬁcial corneal stroma. The epithelium is unaffected, and the stromal opacity is flaky, feathery and diffuse, fading in intensity as it approaches the periphery. This dystrophy was described by Witschel and associates in 1978.57 Posterior polymorphous dystrophy, described by Koeppe in 1916, has an autosomal dominant inheritance pattern with good penetrance and can be asymmetric. The opacities can occur anywhere in the posterior cornea and may either remain stationary or progress slowly. Polymorphous opacities, typically vesicular, are located at the level of Descemet’s membrane. In some cases, when viewed by retro-illumination, the posterior cornea has the appearance of beaten metal. In severe cases, there may be stroma and epithelial edema with or without elevated intraocular pressure58 and peripheral anterior synechiae.59 Congenital hereditary endothelial dystrophy (CHED) was described by Laurence in 1863. It may have autosomal dominant and recessive inheritance patterns with a variable expressivity ranging from minimal posterior corneal changes to severe corneal edema. In contrast with congenital hereditary stromal dystrophy, the corneal thickness is usually increased. Congenital hereditary endothelial dystrophy can present at birth or in the ﬁrst 1 to 2 years of life. Descemet’s membrane appears thickened and gray, and has a peau d’orange texture. The endothelial mosaic may be absent or

irregular. The patient may present with diffuse, bilaterally symmetric corneal edema associated, in some patients, with tearing and photophobia (Figure 6-14). To avoid unnecessary glaucoma surgery, it is crucial to differentiate this disease from congenital glaucoma. A mistaken diagnosis of congenital glaucoma is unlikely because there is no corneal enlargement, the intraocular pressure is normal, and corneal stromal thickness can be up to three times the normal in congenital hereditary endothelial dystrophy.1,5 Congenital hereditary endothelial dystrophy may be associated with glaucoma.60,61 Patients usually are identiﬁed when corneal edema persists after surgical treatment for glaucoma and normalization of intraocular pressure. After treatment with penetrating keratoplasty, histopathological studies of the corneal button showed changes of Descemet’s membrane and attenuation of the endothelium typical of congenital hereditary endothelial dystrophy.60,61 In patients with congenital glaucoma who have persistent and total corneal opaciﬁcation that persists after normalization of intraocular pressure, the combination of congenital hereditary endothelial dystrophy and congenital glaucoma should be suspected. Other causes of corneal opaciﬁcation in early childhood are not commonly confused with congenital glaucoma. Corneal dermoid is a hamartoma that is a rare cause of congenital corneal opaciﬁcation. They may contain mesodermal elements including ﬁbrous tissue, fat, muscle, cartilage, and bone. The severity may vary greatly, from the least severe and most common limbal variety to those that involve the entire cornea and anterior chamber.8 In the milder variety, only the superﬁcial cornea is involved. Peters anomaly is a posterior corneal defect, frequently associated with iris

A

B Figure 6.14 Congenital hereditary endothelial dystrophy (CHED) may be associated with diffuse, bilaterally symmetric corneal edema, which must be distinguished from congenital glaucoma. CHED in an eye, viewed with diffuse illumination (A). Another eye with CHED, viewed by slit beam illumination (B). 37

Primary congenital glaucoma strands connected to the edge of the defect, which causes central corneal opaciﬁcation at birth.

Conditions with overlapping signs of optic nerve abnormalities Congenital malformations of the optic disc must be distinguished from disc changes caused by glaucoma. These pseudoglaucomatous anomalies include congenital optic nerve pits, optic nerve colobomas, and optic nerve hypoplasia.62 The tilted disc syndrome may be associated with hypopigmentation and staphylomatous ectasia in the direction of the tilt. Axial myopia can be associated with a large optic nerve cup or even a tilted disc and accompanying scleral crescent. Optic nerve hypoplasia is associated with a small disc, but difﬁculties in interpretation of the appearance of the disc may be caused by the abnormal termination of the retinal pigment epithelium in the peripapillary area, known as the ‘double ring sign.’ A variant of optic nerve hypoplasia associated with large cups and periventricular leukomalacia may be observed in premature infants.63 Large physiologic cups must also be distinguished from pathological cupping caused by glaucoma. This is not a common problem in the infant where accompanying signs and symptoms are evident, but it can be a problem in the child over 3 years of age who is too young for precise visual ﬁeld testing and in whom the changes secondary to globe elasticity are not evident. Careful examination is essential, and follow-up examination may be required before a deﬁnitive diagnosis can be made. Examination of the family members can be helpful as this may reveal similar optic cups in several members.64

Conditions associated with increased intraocular pressure Inflammatory disease such as maternal rubella syndrome may cause an angle anomaly virtually indistinguishable from that seen in primary infantile glaucoma, with identical clinical stigmata, and a good response to goniotomy (Fig. 6.15). However, the other ocular manifestations of the rubella syndrome in the neonate, including deafness, cardiac anomalies (patent ductus arteriosus, atrial and ventricular septal defects), mental retardation, and cataracts should distinguish this syndrome from primary infantile glaucoma.5 When rubella viremia occurs in the third trimester, anterior chamber angle involvement and glaucoma may occur, without other signs of rubella infection. These cases may be mistakenly identiﬁed as primary infantile glaucoma.4 A transient or permanent corneal edema has been observed in infants with maternal rubella syndrome, even without elevated intraocular pressure.4 Primary congenital glaucoma is diagnosed by the ﬁnding of glaucoma in a child with isolated trabeculodysgenesis and no other ocular diseases that could result in an increased intraocular pressure. The differential diagnosis of primary congenital glaucoma should also include developmental 38

Figure 6-15 Maternal rubella syndrome. The clinical presentation in this child resembles the appearance of primary infantile glaucoma.

glaucomas with associated anomalies, as well as childhood glaucomas secondary to systemic or other ocular disorders, which will be discussed in the subsequent chapter.

Conclusion The clinical features, the diagnostic examination, and the differential diagnosis of primary congenital glaucoma has been discussed. Early diagnosis is important to prevent glaucomatous damage. Any child with tearing, photophobia, blepharospasm, corneal cloudiness, or ocular enlargement should be examined with the possibility of congenital glaucoma in mind. Pressure measurements in all children old enough to cooperate will provide a low yield of glaucoma because of the rarity of this disease in childhood. Nevertheless, when the diagnosis can be made before advanced ﬁeld loss occurs, it is extremely gratifying. Even in children who can not cooperate for pressure measurements, it is a simple matter to examine at the optic nerve head. A cup-to-disc ratio exceeding 0.3 indicates a need for further investigation. Prevention of visual loss is the goal in the treatment of glaucoma. Early diagnosis is essential to accomplish this goal.

References 1. Hoskins HD Jr, Kass MA. Becker-Shaffer’s diagnosis and therapy of the glaucomas, 6th edn. CV Mosby: St. Louis; 1989. 2. Walton DS. Glaucoma in infants and children. In: Harley RD, ed. Pediatric ophthalmology, 2nd edn. WB Saunders: Philadelphia; 1983. 3. Kwitko ML. The pediatric glaucomas. Int Ophthalmol Clin 1981; 21:199–222. 4. Shaffer RN, Weiss DI. The congenital and pediatric glaucomas. CV Mosby: St Louis; 1973. 5. Kwitko ML. Glaucoma in infants and children. Appleton-Century-Crofts: New York; 1973. 6. Scheie HG. Symposium on congenital glaucoma: Diagnosis, clinical course and treatment other than goniotomy. Trans Am Acad Ophthalmol Otolaryngol 1955; 59: 309. 7. Waring GO, Laibson PR, Rodriguez M. Clinical and pathological alteration of Descemet’s membrane with emphasis on endothelial metaplasia. Surv Ophthalmol 1974; 18:325–368.

References 8. Mann I. Developmental abnormalities of the eye. JB Lippincott: Philadelphia; 1957. 9. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176. 10. Morin JD. Congenital glaucoma. Trans Am Ophthalmol Soc 1980; 78:123. 11. Morin JD, Bryars JH. Causes of loss of vision in congenital glaucoma. Arch Ophthalmol 1980; 98:1575–1576. 12. Hass JS. End results of treatment. Trans Am Acad Ophthalmol Otolaryngol 1955; 59:333. 13. Hass J. Principles and problems of therapy in congenital glaucoma. Invest Ophthalmol 1968; 7:140. 14. Barkan O. Goniotomy. Trans Am Acad Ophthalmol 1955; 59:322–332. 15. Scheie HG. Management of infantile glaucoma. Arch Ophthalmol 1959; 62:35. 16. Morin JD, Merin S, Sheppard RW. Primary congenital glaucoma. A survey. Can J Ophthalmol 1974; 9:17–28. 17. Quigley HA. The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 1977; 84:358–370. 18. Broughton WL, Parks MM. An analysis of treatment of congenital glaucoma by goniotomy. Am J Ophthalmol 1981; 91:566–572. 19. Robin AL, Quigley HA, Pollack IP, et al. An analysis of visual acuity, visual ﬁelds and disc cupping in childhood glaucoma. Am J Ophthalmol 1979; 88:847–858. 20. Richardson KT, Shaffer TN. Optic-nerve cupping in congenital glaucoma. Am J Ophthalmol 1966; 62:507–509. 21. Shaffer RN. New concepts in infantile glaucoma. Can J Ophthalmol 1967; 2:243. 22. Shaffer RN. New concepts in infantile glaucoma. Trans Ophthalmol Soc UK 1967; 87:581–590. 23. Shaffer RN, Hetherington J Jr. Glaucomatous disc in infants. A suggested hypothesis for disc cupping. Trans Am Acad Ophthalmol Otolaryngol 1969; 73:929–935. 24. Chandler PA, Grant WM. Glaucoma. Lea and Febiger: Philadelphia; 1980. 25. Iwata K, Sobuek, Imai A, Sakurai I. On the reversibility of glaucomatous disc cupping and the visual ﬁeld. Jpn J Clin Ophthalmol 1977; 31:759. 26. Hetherington J, Shaffer RN, Hoskins HD. The disc in congenital glaucoma. In: Etienne R, Patterson GD, eds. XXII Congress Internationale Ophthalmologie. International glaucoma symposium, Albi, France, 1974, Varseille, France, Diffusion Generale de Librarie, 1975. 27. Anderson DR. Glaucomatous disc changes in infants. In: Symposium on Glaucoma. Trans New Orleans Acad Ophthalmol. CV Mosby: St Louis; 1975:104–155. 28. Kiskis AA, Markowitz SN, Morin JD. Corneal diameter and axial length in congenital glaucoma. Can J Ophthalmol 1985; 20:93–97. 29. Quigley HA. Childhood glaucoma: Results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–226. 30. Dominguez A, Banos S, Alvarez G, Contra GF, Quintela FB. Intraocular pressure measurements in infants under general anesthesia. Am J Ophthalmol 1974; 78:110–116. 31. Van Buskirk EM, Palmer EA. Ofﬁce assessment of young children for glaucoma. Ann Ophthalmol 1979; 11:1749–1751. 32. Radtke ND, Cohen BF. Intraocular pressure measurement in the newborn. Am J Ophthalmol 1974; 78:501–504. 33. Raab EL. Congenital glaucoma. Pers Ophthalmol 1978; 2:35. 34. Ytteborg J. Investigations of the rigidity coefﬁcient in children’s eyes. Acta Ophthalmol 1960; 38:658–674. 35. Kaufman HE, Wind CA, Waltman SR. Validity of Mackay-Marg electronic applanation tonometer in patients with scarred irregular corneas. Am J Ophthalmol 1970; 69:1003–1007. 36. McMillan F, Forster RK. Comparison of Mackay-Marg, Goldmann, and Perkins tonometers in abnormal corneas. Arch Ophthalmol 1975; 93:420–424. 37. West CE, Capella JA, Kaufman HE. Measurement of intraocular pressure with pneumatic applanation tonometer. Am J Ophthalmol 1972; 74:505–509.

38. Hoskins HD, Shaffer RN. Evaluation techniques for congenital glaucomas. J Pediatr Ophthalmol Strabismus 1971; 8:81. 39. Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157. 40. Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485. 41. Worst JGF. The pathogenesis of congenital glaucoma, an embryological and goniosurgical study. CC Thomas: Springﬁeld; 1966. 42. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classiﬁcation of the developmental glaucomas. Arch Ophthalmol 1984; 102:1331–1336. 43. Khoo BK, Koh A, Cheong P, Ho NK. Combination cyclopentolate and phenylephrine for mydriasis in premature infants with heavily pigmented irides. J Pediatr Ophthalmol Strabismus 2000; 37:15–20. 44. Khodadaust AA, Ziai M, Biggs SL. Optic disc in normal newborns. Am J Ophthalmol 1968; 66:502–504. 45. Reibaldi A. Biometric ultrasound in the diagnosis and follow-up of congenital glaucoma. Ann Ophthalmol 1982; 14:707–708. 46. Sampaolesi R, Caruso R. Ocular echometry in the diagnosis of congenital glaucoma. Arch Ophthalmol 1982; 100:574–577. 47. Buschmann W, Bulth K. Ultrasonographic followup examination of congenital glaucoma. Graefe’s Arch Ophthalmol 1983; 61:618. 48. Tarkkanen A, Uusitalo R, Mianowicz J. Ultrasonographic biometry in congenital glaucoma. Acta Ophthalmol 1983; 61:618–623. 49. Kobayashi H, Kiryu J, Kobayashi K, Kondo T. Ultrasound biomicroscopic measurement of anterior chamber angle in premature infants. Br J Ophthalmol 1997; 81:460–464. 50. Kobayashi H, Ono H, Kiryu J, Kobayashi K, Kondo T. Ultrasound biomicroscopic measurement of development of anterior chamber angle. Br J Ophthalmol 1999; 83:559–562. 51. Azuara-Blanco A, Spaeth GL, Araujo SV, et al. Ultrasound biomicroscopy in infantile glaucoma. Ophthalmology 1997; 104:1116–1119. 52. Kolker AE, Hetherington J. Diagnosis and therapy of glaucoma, 4th edn. CV Mosby: St Louis; 1976:276–321. 53. Duke-Elder S. System of ophthalmology, Vol III, Pt 2, Congenital deformities. CV Mosby: St Louis; 1969:548–565. 54. Cibis A, Bunde R. Herpes Simplex virus-induced congenital cataracts. Arch Ophthalmol 1971; 85:220–223. 55. Hagler WS, Walters PV, Nahmias AJ. Ocular involvement in neonatal herpes simplex virus infection. Arch Ophthalmol 1969; 82:169–176. 56. Yamamoto GK, Schulman JD, Schneider JA, Wong VG. Long-term ocular changes in cystinosis: observations in renal transplant recipients. J Pediatr Ophthalmol 1979; 16:21–25. 57. Witschel H, Fine BS, Grutzner P, McTigue JW. Congenital hereditary stromal dystrophy of the cornea. Arch Ophthalmol 1978; 96:1043–1051. 58. Grayson M. The nature of hereditary deep polymorphous dystrophy of the cornea: its association with iris and anterior chamber dysgenesis. Trans Am Ophthalmol Soc 1974; 72:516–559. 59. Cibis GW, Krachmer JH, Phelps CD, Weingeist TA. Iridocorneal adhesions in posterior polymorphous dystrophy. Trans Sect Ophthalmol Acad Ophthalmol Otolaryngol 1976; 81:770–777. 60. Pedersen OO, Rushood A, Olsen EG. Anterior mesenchymal dysgenesis of the eye. Congenital hereditary endothelial dystrophy and congenital glaucoma. Acta Ophthalmol (Copenh) 1989; 67:470–476. 61. Mullaney PB, Risco JM, Teichmann K, Millar L. Congenital hereditary endothelial dystrophy associated with glaucoma. Ophthalmology 1995; 102:186–192. 62. Campbell DG, Netland PA. Stereo atlas of glaucoma. Mosby: St. Louis; 1998. 63. Jacobson L, Hellstrom A, Flodmark O. Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia in children with periventricular leukomalacia. Arch Ophthalmol 1997; 115:1263–1269. 64. Netland PA, Wiggs JL, Dreyer EB. Inheritance of glaucoma and genetic counseling of glaucoma patients. Int Ophthalmol Clin 1993; 33:101–120.

39

Chapter 7 Secondary congenital glaucoma Introduction Axenfeld–Rieger syndrome Peters anomaly Aniridia Glaucoma in the phakomatoses Metabolic diseases Persistent hyperplastic primary vitreous Retinopathy of prematurity (retrolental fibroplasia) Chromosomal anomalies Broad thumb syndrome (Rubenstein–Taybi syndrome) Conclusion

Introduction There are several conditions characterized by developmental defects of the anterior chamber angle with additional ocular and systemic abnormalities, which may be associated with glaucoma. These disorders are typically bilateral, are usually diagnosed at birth or in early childhood, and most have a genetic basis. Furthermore, a large number of other syndromes with ocular and systemic abnormalities may be associated with developmental glaucoma. All these conditions have been grouped under the term secondary congenital glaucoma. The purpose of this chapter is to outline the characteristics of these conditions wherein glaucoma plays a signiﬁcant role.

Axenfeld–Rieger syndrome Axenfeld described, in 1920, a patient with a white line in the posterior aspect of the cornea, near the limbus, and tissue strands extending from the peripheral iris to this prominent line. Beginning in the mid-1930s, Rieger reported cases with similar anterior segment anomalies, but with additional changes in the iris, including corectopia, atrophy, and hole formation. It was also discovered that some of these patients had associated non-ocular developmental defects, especially of the teeth and facial bones. Axenfeld referred to his case as ‘posterior embryotoxon of the cornea,’ while Rieger used the term ‘mesodermal dysgenesis of the cornea and iris.’ In current nomenclature, these conditions are commonly designated by three eponyms. Axenfeld’s anomaly is limited to peripheral anterior segment defects. Rieger’s anomaly includes peripheral anterior segment abnormalities with additional changes in the iris. Rieger syndrome includes ocular

anomalies plus non-ocular developmental defects. Within each category, glaucoma occurs in approximately half the cases. The similarity of anterior chamber angle abnormalities in Axenfeld’s anomaly, Rieger’s anomaly, and Rieger syndrome has led most investigators to agree that these three arbitrary categories represent a spectrum of developmental disorders.1,2 The overlap of ocular anomalies is such that the traditional classiﬁcation is difﬁcult to apply in all patients. For example, the degree of iris stromal atrophy is so slight in some patients that it is hard to know whether the term Axenfeld’s anomaly or Rieger’s anomaly should be used. Indeed, Axenfeld described mild stromal atrophy of the iris in his patient, further compounding the difﬁculty of clearly separating this entity from Rieger’s anomaly. In addition, the association between ocular and non-ocular abnormalities is not always as clear as the traditional classiﬁcation would imply. Although most patients with non-ocular developmental defects have changes in the central iris, as with Rieger’s anomaly, some have only the peripheral ocular abnormalities of Axenfeld’s anomaly3 or no ocular changes at all.4 There are also families in which the ocular and non-ocular anomalies vary considerably among family members. These observations have led many investigators to place all of these conditions within a single diagnostic category. There seems to be no advantage in splitting this spectrum of disorders into sub-categories, since the entire group of patients, irrespective of ocular manifestations, shares the same general features. First, there is a bilateral, developmental disorder of the eyes. Second, there is frequently a family history of the disorder (with an autosomal dominant mode of inheritance). Third, there is no sex predilection. Fourth, there are frequent non-ocular developmental defects. Fifth, there is a high incidence of secondary glaucoma. A single diagnostic category has the advantage not only of eliminating the difﬁculty of selecting an arbitrary subclassiﬁcation, but also of reminding the physician to search for additional ocular and non-ocular disorders in all cases. Most of the names for this spectrum of anomalies were based on presumed common developmental mechanisms, which in turn were dependent upon a particular concept of the related embryology. The terms used include ‘anterior chamber cleavage syndrome,’1 ‘mesodermal dysgenesis of the cornea and iris (dysgenesis mesodermalis corneae et iridis),’5 and ‘primary dysgenesis mesodermalis of the iris.’6 However, the concepts of normal development on which the above terms were based no longer appear to be entirely correct. It was for this reason that the alternative title ‘Axenfeld–Rieger 41

Secondary congenital glaucoma syndrome’ was proposed. This term retains reference to the traditional subclassiﬁcations, but is not dependent upon a particular concept of development, knowledge of which is still incomplete.

The age at which Axenfeld–Rieger syndrome is diagnosed ranges from birth to adulthood, with most cases recognized during infancy or childhood. The diagnosis may result from discovery of an abnormal iris or other ocular anomaly, signs of congenital glaucoma, reduced vision in older patients, or non-ocular anomalies. Other cases are diagnosed during a routine examination, which may have been prompted by a family history of the disorder. There is no apparent racial or sex predilection.5 The family history is often positive for the spectrum of disorders, typically with an autosomal dominant mode of inheritance, although sporadic cases are also common.3 Ocular defects in Axenfeld–Rieger syndrome are typically bilateral. The structures most commonly involved are the peripheral cornea, anterior chamber angle, and iris. The characteristic abnormality of the peripheral cornea is a prominent, anteriorly displaced Schwalbe’s line. This appears on slit-lamp examination as a white line on the posterior cornea near the limbus. In some cases, the line is incomplete, usually limited to the temporal quadrant, while in other patients it may be seen for 360 degrees. Strands of peripheral iris stroma may occasionally be seen by slit-lamp biomicroscopy extending to the prominent Schwalbe’s line. While a prominent Schwalbe’s line is a typical feature of Axenfeld–Reiger syndrome, it is neither a consistent nor pathognomonic ﬁnding. In some cases, the prominent line can only be seen by gonioscopy. A rare case may have other ocular and non-ocular abnormalities of this spectrum of disorders, with grossly normal Schwalbe’s lines.4 More commonly, a patient may have a prominent Schwalbe’s line with no other evidence of the Axenfeld– Rieger syndrome (Fig. 7.1). This isolated defect has been referred to by the term, originally given by Axenfeld, as ‘posterior embryotoxon.’ The prevalence of this condition has been reported ranging from 8%5 to 15%.7,8 While a prominent

Schwalbe’s line, as an isolated ﬁnding, may represent a forme fruste of Axenfeld–Rieger syndrome, it is not included within this spectrum of anomalies, because it is neither associated with an increased incidence of secondary glaucoma nor with non-ocular anomalies. In addition to the isolated ﬁnding, a prominent Schwalbe’s line is occasionally seen in patients with primary congenital glaucoma9 or the iridocorneal endothelial syndrome.10 The cornea is otherwise normal in the typical case of Axenfeld–Rieger syndrome, with the exception of occasional patients with variation in the overall size or shape of the cornea. Microcornea may be seen, although megalocornea, in the absence of known intraocular pressure elevation, is more common. Congenital opacities of the central cornea have also been observed in a few of these cases. The corneal endothelium is typically normal, with the exception of occasional subtle changes consistent with age or longstanding intraocular pressure elevation. The corneal endothelial appearance by specular microscopy reveals distinct cell margins, although mild to moderate variation in the size and shape of the endothelial cells is commonly observed. These changes are more prominent in older patients and in those longstanding glaucoma or previous intraocular surgery. Gonioscopic examination typically reveals a prominent Schwalbe’s line, although there is considerable variation among the patients in the extent to which Schwalbe’s line is enlarged and anteriorly displaced. In occasional cases, the line is suspended from the cornea in some areas by a thin membrane.3,11 Tissue strands bridge the anterior chamber angle from the peripheral iris to the prominent ridge (Fig. 7.2). These strands range in size from threadlike structures to broad bands extending nearly 15 degrees of circumference. In some eyes, only one or two tissue strands are seen, while others have several per quadrant. In addition to the characteristic gonioscopic features of Axenfeld–Rieger syndrome, a more subtle abnormality has also been noted in the anterior chamber angle.3,5,7,8 Beyond the tissue strands, the anterior angle is open and the trabecular meshwork is visible, but the scleral spur is typically obscured by peripheral iris which inserts into the posterior portion of the meshwork. This alteration is distinctly different from the coarser strands of tissue that bridge the angle. In

Figure 7.1 Posterior embryotoxon. The prominent Schwalbe’s line is indicated by the arrow.

Figure 7.2 Axenfeld’s anomaly. The arrowhead indicates the tissue strands that bridge the anterior chamber from the peripheral iris to the prominent Schwalbe’s line (indirect gonioscopic view).

Clinical features

42

Axenfeld–Rieger Syndrome

Figure 7.3 Rieger’s anomaly. Iris abnormalities include iris hole formation with polycoria.

some eyes, this abnormality is continuous for 360 degrees, while in others it involves only one or more quadrants. Aside from peripheral abnormalities, the iris is normal in some eyes with Axenfeld–Rieger syndrome. In other cases, defects of iris range from mild stromal thinning to marked atrophy with hole formation, corectopia and ectropion uvea (Fig. 7.3). When corectopia is present, the pupil is usually displaced toward a prominent peripheral tissue strand, which is often visible by slit-lamp biomicroscopy. The atrophy and hole formation typically occur in the quadrant away from the direction of the corectopia. In a small number of patients with Axenfeld–Rieger syndrome, abnormalities of the central iris have been observed to progress.3,12,13 This is more often seen during the ﬁrst years of life, but may occur at a later time. The progressive changes usually consist of displacement or distortion of the pupil and occasional thinning or hole formation of the iris. Abnormalities of the peripheral iris or anterior chamber angle do not appear to progress after birth, except for occasional thickening of iridocorneal tissue strands.3 Aside from abnormalities of the cornea, anterior chamber angle, and iris, no additional ocular anomalies occur with sufﬁcient regularity to be included as typical features of the Axenfeld–Rieger syndrome. However, many additional ocular abnormalities have been reported in one or more cases or pedigrees. Strabismus has been reported, although it is difﬁcult to know whether this is a primary muscle imbalance or is secondary to reduced visual acuity from the glaucoma. Other rarely associated ocular anomalies include limbal dermoids, cataracts of many types (including congenital), peripheral spoke-like transillumination defects of the iris, retinal detachment, macular degeneration, chorioretinal colobomas, choroidal hypoplasia, and hypoplasias of the optic nerve head.3,5,8 Slightly more than half of the patients with Axenfeld– Rieger syndrome develop glaucoma. This may become manifest during infancy, although it more commonly appears in childhood or young adulthood. Glaucoma seems to occur more often in patients with central iridic changes, although the extent of the defects does not correlate precisely with the presence or severity of the glaucoma. The abundance or paucity of peripheral tissue strands does not correlate with the presence or absence of glaucoma, whereas high insertion of peripheral iris into the trabecular meshwork is associated

with glaucoma.3 The glaucoma associated with Axenfeld– Rieger syndrome is typically difﬁcult to control, often leading to signiﬁcant optic nerve head damage and vision loss. Rare cases have been reported to regress spontaneously. The systemic anomalies most commonly associated with the Axenfeld–Rieger syndrome are developmental defects of the teeth and facial bones. The dental abnormalities include a reduction in crown size (microdontia), a decreased but evenly spaced number of teeth (hypodontia), and a focal absence of teeth (oligodontia or anodontia).14 The teeth most commonly missing are anterior maxillary primary and permanent central incisors. Facial anomalies include maxillary hypoplasia with flattening of the mid-face, a receding upper lip and a prominent lower lip, especially in association with dental hypoplasia. Hypertelorism, telecanthus and a broad flat nose have also been described.5 Anomalies in the region of the pituitary gland are not common, but may be a signiﬁcant ﬁnding associated with the Axenfeld–Rieger syndrome. A primary empty sella syndrome has been documented in several patients,3,15 and one case of congenital parasellar arachnoid cyst has been reported.3 Growth hormone deﬁciency and short stature have also been described in association with this entity.16,17 Other abnormalities reported in association with the Axenfeld–Rieger syndrome include redundant periumbilical skin, hypospadias,18 oculocutaneous albinism,19 heart defects, middle ear deafness, mental deﬁciency, and a variety of neurologic and dermatologic disorders.5

Histopathologic features The central cornea is typically normal, while the peripheral cornea has the characteristic prominent, anteriorly displaced Schwalbe’s line. The Schwalbe’s line is composed of dense collagen and ground substance covered by a monolayer of spindle-shaped cells with basement membrane.3,7,11 The peripheral iris is attached in some areas to the corneoscleral junction by tissue strands which usually connect with the prominent Schwalbe’s line. Occasionally, however, the adhesions insert either anterior or posterior to Schwalbe’s line or on both sides of the ridge.3 The strands consist of either iris stroma, a membrane composed of a monolayer of spindleshaped cells and/or a basement membrane-like layer, or both. A membrane, similar to that seen in association with the iridocorneal tissue strands, has also been observed on the iris, usually on the portion towards which the pupil is distorted.3,5,20 In the quadrants away from the direction of pupillary displacement, the stroma of the iris is often thin or absent, exposing pigment epithelium that may also contain holes. The iris peripheral to the iridocorneal adhesions inserts into the posterior aspect of the trabecular meshwork. The meshwork may be composed of a scant number of attenuated lamellae, which extend from beneath peripheral iris to the prominent Schwalbe’s line and are often compressed, especially in the outer layers. Transmission electron microscopic examination suggests that the apparent compression may be due to incomplete development of the trabecular meshwork. Schlemm’s canal is either rudimentary or absent. 43

Secondary congenital glaucoma

Differential diagnosis The condition most frequently confused with Axenfeld– Rieger syndrome is another spectrum of disorders that has been referred to as the iridocorneal endothelial syndrome.21 Indeed, similarities of certain clinical and histopathologic features of the two disorders have led some investigators to suggest a common mechanism.22 However, comparison of the clinical features of the Axenfeld–Rieger and the iridocorneal endothelial syndromes suggest that these are two distinctly separate entities (Table 7.1).23 The ICE syndrome is composed of three major clinical variations. In Chandler’s syndrome, there are corneal endothelial changes while iris changes are mild to absent.24 In progressive (essential) iris atrophy, iris changes predominate, with marked corectopia, atrophy, and hole formation. In Cogan–Reese (or iris nevus) syndrome, nodular, pigmented lesions of the iris are the hallmark, and may be seen with the entire spectrum of corneal or other iris abnormalities.25,26 In each type of iridocorneal endothelial syndrome, the condition is typically unilateral, usually becomes manifest in young adulthood, and has a predilection for women. There is rarely a positive family history and no additional ocular or systemic abnormalities are associated with the disease.10,27 In all variations, there is an abnormality of the corneal endothelium which frequently leads to edema of the cornea.28 The specular microscopic appearance of the endothelial cells is virtually pathognomonic in the iridocorneal endothelial syndrome, with pleomorphism in shape and size, dark areas within the cells (causing a reversal of the normal shading pattern), and loss of hexagonal margins.29 Ultrastructural studies of corneas with advanced edema reveal markedly abnormal cells lining a thickened, multilayered Descemet’s membrane.28 A characteristic feature common to all forms of the iridocorneal endothelial syndrome is peripheral anterior synechiae, which often extend to or beyond Schwalbe’s line. Progressive closure of the anterior chamber angle leads to secondary glaucoma in a high percentage of patients. The appearance

of the angle and the associated glaucoma are features that may be confused with the Axenfeld–Rieger syndrome, although a prominent Schwalbe’s line is rarely seen in the ICE syndromes.10 Another similarity between the Axenfeld– Rieger and iridocorneal endothelial syndrome is the range of changes observed in the iris. Progressive iris atrophy is characterized by marked corectopia and atrophy of the iris with hole formation, which may also be observed in advanced cases of the Axenfeld–Rieger syndrome. Patients with Cogan– Reese syndrome may have any degree of iris changes, as well as ﬁne nodules or diffuse nevi on the stromal surface.25,26,30 Such nodules are not a typical feature of the Axenfeld–Rieger syndrome, although the association has been described.31 Histopathological studies of the iridocorneal endothelial syndrome have demonstrated a membrane, composed of a single layer of endothelial cells and a basement membrane, extending from the cornea, across the anterior chamber angle, and onto the surface of the iris.32–35 The similarity between this membrane and those seen in Axenfeld–Rieger syndrome is the main feature leading some investigators to suspect a common mechanism for these two syndromes. There may be, however, a difference in the origin of the membranes in these syndromes. According to the theory proposed by Campbell and co-workers for the iridocorneal endothelial syndrome, the fundamental defect is an abnormality of the corneal endothelium which leads to proliferation of the endothelial layer across the anterior chamber angle and over the iris. Subsequent contraction of the membrane pulls the peripheral iris to the anterior chamber angle, forming peripheral anterior synechia and frequently causing secondary glaucoma.32,36,37 The theory of pathogenesis of Axenfeld–Rieger syndrome differs from the mechanism proposed for iridocorneal endothelial syndrome because the membrane is derived not from abnormal corneal endothelium but from retention of the primordial endothelial layer lining the anterior chamber angle during gestation. Several observations are believed to support this concept. In contrast with the iridocorneal endothelial syndrome, the specular microscopic appearance of

Table 7.1 Differences between the Axenfeld–Rieger (A–R) and iridocorneal endothelial (ICE) syndromes and posterior polymorphous dystrophy (PPD) Characteristics

44

A–R syndrome

ICE syndrome

PPD

Age of presentation

Birth

Young adulthood

Birth

Sex predilection

None

Women

None

Laterality

Bilateral

Unilateral

Bilateral

Familial pattern

Frequently

Rarely

Typically

Prominent Schwalbe’s line

Typical

Rarely

Rarely

Non-ocular disorders

Frequent

No

No

Corneal edema

No

Frequent

Occasional

Corneal endothelium

Normal

Abnormal

Abnormal

Proposed origin of membrane

Retention of primordial tissue

Proliferation from abnormal corneal endothelium

Proliferation from abnormal corneal endothelium

Proposed mechanism of secondary glaucoma

Maldevelopment of aqueous outflow system

Outflow obstruction by membrane or peripheral anterior synechiae

Maldevelopment (as in A–R) or membrane-induced (as in ICE)

Axenfeld–Rieger syndrome the corneal endothelium in Axenfeld–Rieger syndrome is within normal limits, allowing for age, chronic intraocular pressure elevation, and surgical intervention. In addition, continuity in the membrane between the iris and the peripheral cornea was rarely observed in histopathologic specimens from patients with the Axenfeld–Rieger syndrome. This is in contrast with the iridocorneal endothelial syndrome, in which the membrane is typically continuous, from the peripheral cornea across the anterior chamber angle and onto the iris.32 In the theories of mechanism for both Axenfeld–Rieger and iridocorneal endothelial syndrome, contraction of a membrane is believed to be the principal cause of the iris changes. The situation in the anterior chamber angle is not the same, however, since the tissue strands in the iridocorneal endothelial syndrome are believed to develop at some point after birth, as the membrane pulls peripheral iris into the angle, while those in the Axenfeld–Rieger syndrome are congenital but may become thicker and shorter by contraction of the associated membrane. Furthermore, the mechanism of the glaucoma differs in the two conditions, in that the membrane over the trabecular meshwork or the peripheral anterior synechia are believed to cause the secondary glaucoma in the iridocorneal endothelial syndrome, whereas maldevelopment of the trabecular meshwork and Schlemm’s canal, and the associated tissue strands, cause the secondary glaucoma in the Axenfeld–Rieger syndrome. Posterior polymorphous dystrophy represents yet another broad spectrum of abnormalities involving the cornea, anterior chamber angle and iris, which may be confused with both the Axenfeld–Rieger and iridocorneal endothelial syndromes (Table 7.1).38 posterior polymorphous dystrophy resembles the Axenfeld–Rieger syndrome in that it is congenital, typically with autosomal dominant inheritance, has bilateral ocular involvement, and has no signiﬁcant race or sex predilection.39 It resembles the iridocorneal endothelial syndrome, however, in that association of glaucoma is usually not recognized until adulthood and corneal edema may be present.40,41 The common feature throughout the spectrum of posterior polymorphous dystrophy is an abnormality of the corneal endothelium and Descemet’s membrane, giving the slitlamp appearance of blisters or vesicles on the posterior surface of the cornea, which are often linear or in groups and surrounded by an area of gray haze (Fig. 7.4).40,41 Most patients remain asymptomatic, although secondary stromal and epithelial edema occurs in some cases. An even smaller

number of patients may have broad iridocorneal adhesions, occasionally with corectopia, ectropion uvea, and rarefaction of the iris.41,42 Some of these cases will be associated with glaucoma, while other patients with posterior polymorphous dystrophy may have glaucoma in the absence of these anterior chamber angle and iris changes. In those cases with glaucoma and iridocorneal adhesions, ultrastructural studies have revealed a layer of Descemet’s membrane and transformed endothelial cells with epithelial characteristics covering the trabecular beams and iris.35 It has been postulated that this layer extends down from the abnormal corneal endothelium and that subsequent contraction leads to the secondary synechiae formation and iris changes,40 similar to that which has been proposed for the iridocorneal endothelial syndrome.32 In the other form of glaucoma associated with posterior polymorphous dystrophy, a high insertion of the iris into the posterior trabecular meshwork has been observed by gonioscopy and microscopic examination, and ultrastructural examination revealed collapse of the trabecular beams.43 These changes resemble those seen in primary congenital glaucoma5 and Axenfeld– Rieger syndrome,3 suggesting a developmental anomaly of the anterior chamber angle in this variation of posterior polymorphous dystrophy.43 It may be that this abnormality of the angle represents a common pathway, which leads to glaucoma in several developmental disorders. Distinctions between the Axenfeld–Rieger and iridocorneal endothelial syndromes and the posterior polymorphous dystrophy are summarized in Table 7.1. Peters anomaly is a developmental abnormality involving the central cornea, iris, and the lens. Similar changes have been reported in association with the peripheral iris and angle abnormalities of the Axenfeld–Rieger syndrome, and the two conditions were once included in a single category of developmental disorders.1,2 However, this association is rare and the mechanisms for the two groups of developmental disorders are distinctly different. Patients may have congenital hypoplasia of the iris without the anterior chamber angle defect of Axenfeld–Rieger syndrome or any other ocular abnormality. Iris hypoplasia has also been reported in association in juvenile-onset glaucoma with autosomal dominant inheritance. Congenital ectropion uvea is a rare, non-progressive anomaly characterized by the presence of pigment epithelium on the stroma of the iris.44–47 It may be an isolated ﬁnding, or may occur in association with ptosis (Fig. 7.5). Congenital

Figure 7.4 Posterior polymorphous dystrophy associated with glaucoma. Opacities resembling blisters or vesicles may be identified on the posterior surface of the cornea (A). The opacities at the level of Descemet’s membrane may form a linear pattern (B).

A

B

45

Secondary congenital glaucoma

A

B

C

Figure 7.5 Congenital ectropion uvea. A non-progressive extension of pigment epithelium onto the anterior surface of the iris (A). The anterior surface of the iris may have a smooth appearance (B), and may occur in association with ptosis (C).

ectropion uvea may also occur in association with systemic anomalies, including neuroﬁbromatosis, facial hemiatrophy, and the Prader–Willi syndrome.44 Glaucoma is present in a high percentage of cases, and ectropion uvea may be confused with that found in some cases in the Axenfeld–Rieger syndrome. The extent of ectropion uvea usually remains unchanged, but progressive changes have been identiﬁed.48 In iridoschisis, there is bilateral separation and dissolution of the stromal layers of the iris, which may be associated with glaucoma.49 Iridoschisis differs from Axenfeld–Rieger syndrome and other abnormalities of the iris by the age of onset in the 6th or 7th decade of life. The rudimentary iris and anterior chamber abnormalities with associated glaucoma in aniridia may, in some cases, lead to confusion with the Axenfeld–Rieger syndrome. Ectopia lentis et pupillae is an autosomal recessive condition that is characterized by bilateral displacement of the lens and pupil,50 with the two structures typically displaced in opposite directions. The corectopia in this disorder may resemble that of the Axenfeld–Rieger syndrome, but the absence of anterior chamber angle defects is a differentiating feature. In oculodentodigital dysplasia, the dental abnormalities are similar to those seen in the Axenfeld–Rieger syndrome. In addition, these patients may occasionally have mild stromal hypoplasia of the iris, anterior chamber angle defects, microophthalmia, and glaucoma.51

Management of Axenfeld–Rieger syndrome The primary concern regarding the management of ocular defects in a patient with the Axenfeld–Rieger syndrome is detection and control of the associated glaucoma. Intraocular pressure elevation most often develops between childhood and early adulthood, but may appear in infancy, or in rare cases, not until the elderly years.3 Therefore, patients with the Axenfeld–Rieger syndrome must be followed for suspicion of glaucoma throughout their life. Patients should also be examined for associated ocular and systemic abnormalities.52 46

With the exception of infantile cases, medical therapy should usually be tried before surgical intervention is recommended. Pilocarpine and other miotics are often ineffective, and drugs which reduce aqueous production, such as betablockers and carbonic anhydrase inhibitors are most likely to be beneﬁcial. Laser surgery has not been found effective in managing the glaucoma in the Axenfeld–Rieger syndrome. Options for conventional surgery include goniotomy, trabeculotomy, and trabeculectomy. The former two have been utilized in infantile cases with limited success. Goniotomy may be impeded due to iris strands. Trabeculectomy is the surgical procedure of choice for most patients with glaucoma secondary to the Axenfeld–Rieger syndrome. Difﬁculty with intraoperative airway management has been described in a child with Axenfeld–Rieger syndrome.53

Peters anomaly In 1897, Von Hippel reported a case of buphthalmos with bilateral central corneal opacities and adhesions from these defects to the iris. Peters, beginning in 1906, described similar patients with what has been generally known as Peters anomaly.

General features Most cases are sporadic, although there is evidence of autosomal recessive inheritance, and chromosomal defects have been described.54 The condition is present at birth and is usually bilateral. It typically occurs in the absence of additional abnormalities, although rare associations with various systemic and other ocular anomalies have been reported.

Clinicopathologic features The hallmark of Peters anomaly is a central defect in Descemet’s membrane and corneal endothelium with thinning and opaciﬁcation of the corresponding area of corneal stroma (Fig. 7.6).55–58 Adhesions may extend from the borders of this

Aniridia

Glaucoma anomaly

associated

with

Peters

Approximately half of the patients with Peters anomaly will develop glaucoma, which is frequently present at birth. The mechanism of the glaucoma is uncertain. The anterior chamber angle is usually grossly normal by clinical examination. One histopathological report of the eye of a young child with Peters anomaly described changes in the trabecular meshwork that are characteristic of aging.61 Patients with glaucoma may be at increased risk for other systemic abnormalities.62 A

Differential diagnosis

B Figure 7.6 Schematic representation of Peters anomaly (A). Abnormalities include a central defect in Descemet’s membrane and the corneal endothelium, adhesions extending from the borders of this defect to the iris and lens, and frequently cataract. Clinical appearance of an infant with Peters anomaly (B). A central corneal leukoma is present. The day before the photograph, the child underwent trabeculotomy combined with trabeculectomy for marked elevation of intraocular pressure despite medical therapy.

defect to the iris. Bowman’s membrane may also be absent centrally.57,58 The disorder has been subdivided into three groups, each of which may have more than one pathogenic mechanism: those not associated with keratolenticular contact or cataract, those associated with keratolenticular contact or cataract, and those associated with Axenfeld– Rieger syndrome.56 The association of Peters anomaly with Axenfeld–Rieger syndrome is rare. Some cases of Peters anomaly are not associated with keratolenticular contact or cataract. In these cases, the defect in Descemet’s membrane may represent primary failure of corneal endothelium to develop. However, rare cases may be secondary to intrauterine inflammation,59 which was originally postulated by Von Hippel and gave rise to the term ‘Von Hippel’s’ internal corneal ulcer. Other cases are associated with keratolenticular contact or cataract. Most histopathologic studies of this variation suggest that the lens developed normally and was then secondarily pushed forward against the cornea by one of several mechanisms, causing the loss of Descemet’s membrane.56,57,60 It is also possible that some cases may result from incomplete separation of the lens vesicle from the surface ectoderm.

The corneal clouding of Peters anomaly must be distinguished from primary congenital glaucoma, birth trauma, the mucopolysaccharidoses, and congenital hereditary corneal dystrophy. In addition, posterior keratoconus may be confused with Peters anomaly. Posterior keratoconus is a rare disorder that is characterized by a thinning of the central corneal stroma, with excessive curvature of the posterior corneal surface and variable overlying stromal haze.2,63 An ultrasound study revealed a multilayered Descemet’s membrane with abnormal anterior banding and localized posterior excresences. Glaucoma is rarely associated with posterior keratoconus. Congenital corneal leukomas and staphylomas represent severe forms of central dysgenesis of the anterior ocular segment and are frequently associated with glaucoma.

Management All infants and children with cloudy corneas must be examined carefully for the possibility of associated glaucoma, which usually requires surgical intervention. Initial trabeculectomy may offer the best chance of success. Penetrating keratoplasty is also frequently necessary. Visual outcomes are poor due to the presence of congenital anterior and posterior segment anomalies, structural defects of the central nervous system, cognitive dysfunction, and amblyopia, as well as postoperative complications such as graft failure, cataract, inoperable retinal detachment, and phthisis.64,65

Aniridia Aniridia (Greek: absence of iris) is a bilateral, uncommon panocular disorder affecting not only the iris, but also the cornea, anterior chamber angle, lens, retina and optic nerve. The name ‘aniridia,’ however, is a misnomer, since a small portion of the iris tissue can be present. The term ‘iridemia’ better describes the condition than does ‘aniridia.’ Since Barrata’s ﬁrst description of aniridia in 1818, the ophthalmic literature has contained many scattered reports on the subject. Most cases are inherited by autosomal dominant transmission,66 although sporadic cases also occur. Other patients, especially those with mental retardation, have an autosomal 47

Secondary congenital glaucoma recessive mode of inheritance. No signiﬁcant sexual or racial predilection for aniridia has been described. Four phenotypes of aniridia have been identiﬁed on the basis of associated ocular and systemic abnormalities.67 One phenotype is aniridia with predominant iris changes and normal visual acuity. Another phenotype is aniridia associated with foveal hypoplasia, nystagmus, corneal pannus, glaucoma, and reduced vision. The third type is aniridia associated with Wilm’s tumor (the aniridia–Wilm’s tumor syndrome) or other genitourinary anomalies. The fourth phenotype is aniridia associated with mental retardation.

Clinical manifestations Decreased vision is generally associated with aniridia.68–72 The majority of ophthalmic manifestations occurring with aniridia are the result of various associated ocular abnormalities, including cataracts, glaucoma, corneal dystrophy, nystagmus, photophobia, strabismus, ectopia lentis, optic nerve hypoplasia, and poor foveal reflex. Poor foveal development may occur in the postnatal period in some cases. The ophthalmic complications associated with aniridia, especially cataracts, glaucoma, and corneal opaciﬁcation, are often responsible for progressive loss of vision. Photophobia is often present in affected patients, and is due to absence of a normal pupil and excessive light stimulation. A characteristic facial expression in many children is narrowing of the palpebral ﬁssure and furrowing of the brow (Fig. 7.7).73,74 There is variability in the iris conﬁguration in aniridia, ranging from almost total absence to mild hypoplasia of the iris (Fig. 7.8). Although early reports described cases in which the iris appeared to be completely missing clinically, complete gonioscopic examination was not performed. Ocular colobomas associated with aniridia have been reported among individuals in the same family in the early literature. Aniridia is still considered by some to be one of the colobomatous disorders.75 Congenital glaucoma with or without buphthalmos is rare in infants with aniridia; however, the reported incidence of glaucoma later in childhood is 6% to 75%. The higher

Figure 7.7 Aniridia. Photophobia with narrowing of the palpebral fissure and furrowing of the brow.

ﬁgures were reported from glaucoma centers and probably represent an overestimation of the true incidence because of the referral nature of the institutions. Routine gonioscopic examination is important to detect anatomic changes in the angle structures that may progress to angle closure. During the ﬁrst few years of life, the trabecular meshwork appears open and is not covered by iris tissue. Grant and Walton found that progressive change in the angle structures may occur during the ﬁrst two decades of life in those patients who will develop glaucoma.74,76 These changes include attachment of the rudimentary iris to an anterior position, thereby covering the ﬁltration area of the trabecular meshwork. Most of the ﬁltration area is covered by the iris remnant in patients who will develop glaucoma. Glaucoma secondary to intumescent lens changes or ectopia lentis has been reported in aniridia. Ectopia lentis has been reported, ranging from 0% up to 56% of patients with aniridia. Failure to detect mild subluxations of the lens may be the reason ectopia lentis has not been reported by some investigators. Hypoplastic ciliary processes have been reported in pathologic specimens from patients with aniridia, but no defects in zonules or the pars plana have been reported.73 Cataracts occur frequently and at a young age in aniridia.67,70 Lens opacities develop in 50% to 85% of patients, usually during the ﬁrst two decades of life. Although many aniridics have poor vision during adolescence secondary to foveal Figure 7.8 Aniridia. An iris remnant is present. The lens and cornea are clear in the right eye (A). There is corneal edema due to elevated intraocular pressure in the left eye (B). The corneal edema is more prominent centrally.

A

48

B

Glaucoma in the Phakomatoses hypoplasia and corneal opaciﬁcation, cataracts may further compromise vision. Frequently, at birth, small anterior and posterior lens opacities may be noted, but these do not usually cause signiﬁcant visual difﬁculty. Cortical, subcapsular, and lamellar opacities often develop by the teenage years and may require lens extraction. Corneal abnormalities are common in aniridia. In a high proportion of patients, a corneal pannus and opacity begins in the peripheral cornea in early life and advances towards the center of the cornea with increasing age. Because the corneal abnormality in aniridia is vascularized and inflamed, it is not included among the group of diseases known as dystrophies. Microcornea77 has been reported in association with aniridia. Increased central corneal thickness has been reported in patients with aniridia,78 which may lead to inaccuracy (overestimation) of applanation tonometry measurement of intraocular pressure in some patients. Layman and coworkers70 suggested that the majority of aniridia patients have optic nerves that are hypoplastic. However, optic nerve hypoplasia is often difﬁcult to document in the aniridia patient because of nystagmus and poor visibility secondary to cornea and lens involvement. Poor retinal and macular development seen in many aniridics probably contributes to or is entirely responsible for the optic nerve hypoplasia. Pendular nystagmus is present in the majority of patients with aniridia. Most investigators believe the nystagmus is secondary to macular hypoplasia.67,70 Strabismus is common in aniridic patients, often an esotropia. High refractive errors are common and a careful cycloplegic refraction is necessary in affected children. Asymmetric visual loss in aniridic children may occur from amblyopia secondary to strabismus or anisometropia. Aniridia has also been reported in association with Marfan syndrome, Hallerman–Streiff syndrome, and sometimes with ptosis. Different mechanisms have been proposed for the elevation of intraocular pressure in aniridic patients. There may be abnormal function of the anterior chamber angle, with or without absence of Schlemm’s canal. Peripheral anterior synechiae may cause secondary angle closure.74,76 Secondary angle closure may develop following cataract extraction or glaucoma procedure. The anterior chamber angle may be open, with elevation of intraocular pressure. Unsuccessful argon laser trabeculoplasty may also be associated with elevated intraocular pressure.

most cases. Aniridic glaucoma requiring surgical treatment occurs in up to half of patients. Goniotomy is of limited value in advanced cases, but early goniotomy to separate the iris and the trabecular meshwork may prevent the development of glaucoma.66,76,79 Initial trabeculotomy80 or trabeculotomy combined with trabeculectomy81 may also be effective. Trabeculectomy alone is often unsuccessful,82 although trabeculectomy with mitomycin C may be a useful option.83 A glaucoma drainage implant may have a lasting beneﬁt in some cases.82,84 Cyclophotocoagulation may have a role in some patients with intractable glaucoma as a temporizing or adjunctive measure.85

Glaucoma in the phakomatoses The phakomatoses (phakos = birthmark) or disseminated hamartomatoses, are a group of ophthalmologically important hereditary disorders exhibiting variable penetrance and expressivity. These disorders are characterized by the formation of hamartias and hamartomas in the eye, central nervous system, skin, and viscera. The classic features of the phakomatoses include nontumorous growths on the skin or mucous membranes that arise from cells normally found in the tissue at the involved site of growth (hamartias). Also, there are localized tumors arising from cells normally found in the tissue at the site of growth (hamartomas). There may be true neoplasms originating from undifferentiated embryonic cells of differentiated mature cells as well as other associated congenital abnormalities. In phakomatoses, derivatives of all three embryonic layers may be affected. Some of the phakomatoses are commonly associated with glaucoma, whereas others are occasionally or rarely associated, or not associated with glaucoma (Table 7.2). Sturge–Weber syndrome (encephalotrigeminal angiomatosis) is commonly associated with glaucoma (Fig. 7.9). Glaucoma is occasionally a manifestation of other phakomatoses, including neuroﬁbromatosis (Von Recklinghausen), angiomatosis retinae (Von Hippel–Lindau), and oculodermal melanocytosis (nevus of Ota, Fig. 7.10). Glaucoma in the phakomatoses86 can develop through a number of different mechanisms, even within a single disease entity. Table 7.2 Glaucoma associated with phakomatoses Commonly associated with glaucoma Encephalotrigeminal angiomatosis (Sturge–Weber syndrome)

Differential diagnosis of aniridia Aniridia must be differentiated from other disorders, including iris coloboma (typical or atypical), corectopia, iridocorneal endothelial syndrome, anterior chamber cleavage syndromes, and colobomatous microphthalmia.

Management of glaucoma in aniridia Conventional medical therapy may control the intraocular pressure initially, but eventually proves to be inadequate in

Occasionally associated with glaucoma Neurofibromatosis (Von Recklinghausen) Angiomatosis retinae (Von Hippel–Lindau) Oculodermal melanocytosis (nevus of Ota) Rarely associated with glaucoma Basal cell nevus syndrome Tuberous sclerosis (Bourneville) Klippel–Trenaunay–Weber (in pure form) Diffuse congenital hemangiomatosis Unassociated with glaucoma Ataxia–telangiectasia (Louis–Bar) Racemose angioma of the retina (Wyburn–Mason)

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Secondary congenital glaucoma

B

A

C

Figure 7.9 Sturge–Weber syndrome (encephalotrigeminal angiomatosis). Amblyopia therapy in a child with unilateral nevus flammeus associated with glaucoma in the left eye (A). Bilateral is less common than unilateral involvement (B). The soft palate may be affected (C). Note the soft tissue hypertrophy in the upper lip on the affected side (C). Prominent episcleral vessels in a patient with Sturge–Weber syndrome (D).

D

B Figure 7.10 Nevus of Ota (oculodermal melanocytosis). Bilateral periocular hyperpigmentation (A), which is less common compared with uniocular involvement. Episcleral melanosis may have a slate gray appearance (B), in contrast with the brown appearance of the superficial pigmentation immediately adjacent to the limbus. A

Diagnosis of glaucoma is frequently straightforward, based on the presence of elevated intraocular pressure, buphthalmos, and other signs of glaucoma in infancy or early childhood, and based on elevated intraocular pressure in children and adults. Optimal treatment, however, often depends on the determination and analysis of the underlying mechanisms of the glaucoma. Although there is no universal mechanism to explain the pathogenesis of glaucoma in the phakomatoses, there 50

are similarities among the syndromes. Tissue hypertrophy and developmental abnormalities have been postulated to cause ocular hypertension in both neuroﬁbromatosis and encephalotrigeminal angiomatosis, or melanocytes in oculodermal melanocytosis. A ciliary body or choroidal neuroﬁbroma or an iris hemangioma may cause the iris to obstruct the angle. Neovascular glaucoma has been reported in neuroﬁbromatosis, encephalotrigeminal angiomatosis, angiomatosis retinae, and tuberous sclerosis. Elevated

Retinopathy of prematurity (retrolental fibroplasia) episcleral venous pressure may occur in encephalotrigeminal angiomatosis, which may increase the risk of complications associated with glaucoma surgery.

Metabolic diseases Oculocerebrorenal syndrome of Lowe Oculocerebrorenal syndrome (Lowe syndrome) features increased organic aciduria, systemic acidosis, ketonuria, glycosuria, proteinuria, emotional irritability, and mental retardation. The blood shows a decreased carbon dioxide and a decrease in serum phosphorus. The inheritance pattern is X-linked recessive, and mothers who are carriers of the trait may have characteristic punctate lens opacities. The ophthalmic ﬁndings include congenital cataracts, nystagmus, blue sclera, and, in patients with glaucoma, corneal edema and bilateral corneal opaciﬁcation (Fig. 7.11). Glaucoma is noted in approximately two-thirds of the patients. Patients may have microphthalmia, which may present with elevated intraocular pressure. The mechanism of the glaucoma is related to faulty development of the ﬁltration angle. Gonioscopy reveals minor anatomic defects, including poor visualization of the scleral spur and a narrow ciliary body band. Ophthalmic treatment includes cataract extraction and control of glaucoma. Glaucoma may respond to goniotomy or trabeculotomy, although ﬁltering surgery may be required. Comanagement with a pediatrician is required for the metabolic disorder.

Homocystinuria Homocystinuria is a metabolic abnormality with a defect in the enzyme cystathionine synthetase. It is inherited as an autosomal recessive disorder. The patients are characteristically lightly pigmented with blond hair and blue eyes. Ocular abnormalities include ectopia lentis,87 retinal detachment, and glaucoma. The lens is usually subluxated inferiorly, but may move anteriorly, resulting in pupillary block glaucoma.

Figure 7.11 Lowe’s syndrome (oculocerebrorenal syndrome). This infant had bilateral cataracts and renal tubular dysfunction (Fanconi syndrome). He subsequently manifested elevated intraocular pressure, hypotonia, frontal bossing, and developmental delay. His mother had punctate lens opacities, most apparent after dilation of the pupil with retroillumination.

When the dislocated lens causes angle closure, treatment consists of dilatation of the pupil and peripheral iridectomy to break the pupillary block. If possible, iridectomy should be done with laser, because patients may have an increased risk of thromboembolic phenomena with general anesthesia. Lens extraction is required if the lens has dislocated into the anterior chamber.

Sulfite oxidase deficiency Sulﬁte oxidase deﬁciency is characterized by severe neurological abnormalities, mental retardation, and dislocation of the lens. The syndrome is due to defective activity of the enzyme that normally catalyzes the conversion of sulﬁte to sulfate. Death usually occurs in early childhood. Glaucoma is managed in the same fashion as in homocystinuria.

Persistent hyperplastic primary vitreous Persistent hyperplastic primary vitreous typically occurs unilaterally in a microphthalmic eye. It results from failure of atrophy of the primary vitreous and its vascular structures. A retrolental ﬁbrovascular membrane can attach to the posterior aspect of the lens, as well as to the ciliary processes. The membrane may appear as a whitish mass in the pupil, giving rise to leukocoria. Secondary angle closure glaucoma can occur because of swelling of the lens and contraction of the retrolental membrane, which pushes the lens further forward. Hemorrhages into the eye may also result in glaucoma. Removal of the lens and membrane may prevent closure of the angle and is indicated if the angle is narrowing. Peripheral iridectomy can delay the need for lens extraction, but the angle must be observed carefully for progressive closure.

Retinopathy of prematurity (retrolental fibroplasia) Retinopathy of prematurity is often associated with prematurity of the newborn and oxygen therapy. It is typically bilateral and fairly symmetric, although it can present asymmetrically. Occasionally the disease occurs in full-term infants and in those without any oxygen therapy. Retinal blood vessels reach the ora serrata nasally at eight months gestation but do not vascularize the temporal retina until shortly after birth. The retinal vessels only appear susceptible to oxygen damage before their complete vascularization, which accounts for the propensity for retrolental ﬁbroplasia to occur temporally. The initial effect of oxygen on the retinal blood vessels is vasoconstriction. When the infant is placed in normal air, vascular endothelial proliferation may occur adjacent to vessels that were constricted and closed during oxygen therapy. Regression is common in the earlier stages of the process, but with more advanced disease neovascularization may develop through the internal limiting membrane onto the retinal 51

Secondary congenital glaucoma surface and into the vitreous. If these advanced stages are reached, vitreous hemorrhage and ﬁbrosis, and retinal detachment may occur. The development of these retrolental ﬁbrotic membranes can cause a forward displacement of the lens and iris, which may lead to angle closure glaucoma, usually with some degrees of pupillary block.88 Iridectomy can be helpful in relieving the pupillary block.89 Lens removal with removal of the retrolental membranes may be indicated in selected cases.

Chromosomal anomalies Several types of chromosomal defects are often associated with developmental glaucoma. These include Trisomy 21 (Down syndrome), Trisomy D (13–15) syndrome, Trisomy 18 (Edward syndrome), and Turner syndrome (XO). Multiple ocular and systemic defects may be evident, in association with a large variety of presentations. The necessity for surgical and medical management must be individualized to each patient because some of these patients have a limited life expectancy. If isolated trabeculodysgenesis is evident on examination, a goniotomy or trabeculotomy would be the initial procedure.

Broad thumb syndrome (Rubenstein–Taybi syndrome) Broad thumbs and great toes are the most evident abnormalities in this syndrome. They may occur in association with mental and motor retardation, lid colobomata, cataract, as well as congenital glaucoma.90 Large physiologic optic disc cupping without glaucoma also can be seen in these patients. In patients with glaucoma, goniotomy or trabeculotomy can be successful in controlling the glaucoma.

Conclusion The diagnosis and management of some of the important secondary congenital glaucomas have been discussed in this chapter. In the management of the secondary congenital glaucomas, identiﬁcation of the underlying mechanism for the glaucoma determines the appropriate therapeutic strategy. The necessity for surgical and medical management must be individualized to each patient, and a multidisciplinary approach must be undertaken whenever necessary.

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6. Rieger H. Dysgenesis mesodermalis corneae et iridis. Z Augenheilkd 1935; 86:333. 7. Burian HM, Braley AE, Allen L. External and gonioscopic visibility of the ring of Schwalbe and the trabecular zone: an interpretation of the posterior corneal embryotoxon and the so-called congenital hyaline membranes on the posterior corneal surface. Trans Am Ophthalmol Soc 1954; 51:389–428. 8. Burian HM, Braley AE, Allen L. Visibility of the ring of Schwalbe and the trabecular zone: an interpretation of the posterior corneal embryotoxon and the so-called congenital hyaline membranes on the posterior corneal surface. Arch Ophthalmol 1955; 53:767–782. 9. Maumenee AE. Further observations of the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176. 10. Shields MB, Campbell DG, Simmons RJ. The essential iris atrophies. Am J Ophthalmol 1978; 85:749–759. 11. Wolter JR, Sandall GS, Fralick FB. Mesodermal dysgenesis of anterior eye with a partially separated posterior embryotoxon. J Pediatr Ophthalmol 1967; 4:41–46. 12. Cross HE, Jorgenson RJ, Levin LS, Kelly TE. The Rieger syndrome: an autosomal dominant disorder with ocular, dental and systemic abnormalities. Perspect Ophthalmol 1979; 3:3–16. 13. Dark AJ, Kirkham TH. Congenital corneal opacities in a patient with Rieger’s anomaly and Down’s syndrome. Br J Ophthalmol 1968; 52:631–635. 14. Wesley RK, Baker JD, Golnick AL. Rieger’s syndrome (oligodontia and primary mesodermal dysgenesis of the iris): clinical features and report of an isolated case. J Pediatr Ophthalmol Strabismus 1978; 15:67–70. 15. Kleinmann RE, Kazarian EL, Raptopoulos V, Braverman LE. Primary empty sella and Reiger’s anomaly of the anterior chamber of the eye: a familial syndrome. N Engl J Med 1981; 304:90–93. 16. Feingold M, Shiere F, Fogels HR, Donaldson D. Rieger’s syndrome. Pediatrics 1969; 44:564–569. 17. Sadeghi-Nejad A, Senior B. Autosomal dominant transmission of isolated growth hormone deﬁciency in iris-dental dysplasia (Rieger’s syndrome). J Pediatr 1974; 85:644–648. 18. Jorgenson RJ, Levin LS, Cross HE, Yoder F, Kelly TE. The Rieger syndrome. Am J Med Genet 1978; 2:307–318. 19. Lubin JR. Oculocutaneous albinism associated with corneal mesodermal dysgenesis. Am J Ophthalmol 1981; 91:347–350. 20. Troeber R, Rochels R. Histological ﬁndings in dysgenesis mesodermalis iridis et corneae Rieger. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1980; 213:169–174. 21. Yanoff M. Discussion of Shields MB, McCracken JS, Klintworth GK, Campbell DG: corneal oedema in essential iris atrophy. Ophthalmology 1979; 86:1549–1550. 22. Kupfer C, Kaiser-Kupfer MI, Datiles M, McCain L. The contralateral eye in the iridocorneal endothelial (ICE) syndrome. Ophthalmology 1983; 90:1343–1350. 23. Shields MB. Axenfeld-Rieger and iridocorneal endothelial syndromes: two spectra of disease with striking similarities and differences. J Glaucoma 2001; 10 (Suppl 1):S36–S38. 24. Chandler PA. Atrophy of the stroma of the iris: endothelial dystrophy, corneal edema, and glaucoma. Am J Ophthalmol 1956; 41:607–615. 25. Cogan DG, Reese AB. A syndrome of iris nodules, ectopic Descemet’s membrane, and unilateral glaucoma. Doc Ophthalmol 1969; 26:424–433. 26. Scheie HG, Yanoff M. Iris nevus (Cogan–Reese) syndrome. A cause of unilateral glaucoma. Arch Ophthalmol 1975; 93:963–970. 27. Shields MB. Progressive essential iris atrophy, Chandler’s syndrome, and the iris nevus (Cogan-Reese) syndrome: a spectrum of disease. Surv Ophthalmol 1979; 24:3–20. 28. Shields MB, McCracken JS, Klintsworth GK, et al. Corneal edema in essential iris atrophy. Ophthalmology 1979; 86:1533–1548. 29. Hirst LW, Quigley HA, Stark WJ, et al. Specular microscopy of iridocorneal endothelial syndrome. Am J Ophthalmol 1980; 89:11–21. 30. Shields MB, Campbell DG, Simmons RJ, et al. Iris nodules in essential iris atrophy. Arch Ophthalmol 1976; 94:406–410. 31. Theil R. Atlas of disease of the eye, Vol 2. Elsevier: New York; 1963:222–223. 32. Campbell DG, Shields MB, Smith TR. The corneal endothelium and the spectrum of essential iris atrophy. Am J Ophthalmol 1978; 86:317–324. 33. Rodrigues MM, Streeten BW, Spaeth GL. Chandler’s syndrome as a variant of essential iris atrophy: a clinicopathological study. Arch Ophthalmol 1978; 96:643–652. 34. Eagle RC Jr, Font RL, Yanoff M, et al. Proliferative endotheliopathy with iris abnormalities: the iridocorneal endothelial syndrome. Arch Ophthalmol 1979; 97:2104–2111. 35. Rodrigues MM, Phelps CD, Krachmer JH, et al. Glaucoma due to endothelialization of the anterior chamber angle: a comparison of posterior polymorphous dystrophy of the cornea and Chandler’s syndrome. Arch Ophthalmol 1980; 98:688–696.

References 36. Campbell DG. Formation of iris nodules in primary proliferative endothelial degeneration. Presented at the meeting of the Association for Research in Vision and Ophthalmology, Sarasota, FL, April 30–May 4, 1979. 37. Eagle RC Jr, Font RL, Yanoff M, et al. The iris nevus (Cogon-Reese) syndrome: light and electron microscopic observations. Br J Ophthalmol 1980; 64:446–452. 38. Anderson NJ, Badawi DY, Grossniklaus HE, Stulting RD. Posterior polymorphous membranous dystrophy with overlapping features of iridocorneal syndrome. Arch Ophthalmol 2001; 119:624–625. 39. Waring GO III, Rodrigues MM, Laibson PR. Corneal dystrophies II. Endothelial dystrophy. Surv Ophthalmol 1978; 23:147–168. 40. Cibis GW, Krachmer JH, Phelps CD, Weingeist TA. The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol 1977; 95:1529–1537. 41. Grayson M. The nature of hereditary deep polymorphous dystrophy of the cornea: its association with iris and anterior chamber dysgenesis. Trans Am Ophthalmol Soc 1974; 72:516–559. 42. Cibis GW, Krachmer JH, Phelps CD, Weingeist TA. Iridocorneal adhesions in posterior polymorphous dystrophy. Trans Am Acad Ophthalmol Otolarygnol 1976; 81:770–777. 43. Bourgeois J, Shields MB, Thresher R. Open angle glaucoma associated with posterior polymorphous dystrophy. Ophthalmology 1984; 91:420–423. 44. Ritch R, Forbes M, Hetherington J Jr, Harrison R, Podos SM. Congenital ectropion uveae with glaucoma. Ophthalmology 1984; 91:326–331. 45. Gramer E, Krieglstein GK. Infantile glaucoma in unilateral uveal ectropion. Graefe’s Arch Ophthalmol 1979; 211:215–219. 46. Dowling JL Jr, Albert DM, Nelson LB, Walton DS. Primary glaucoma associated with iridotrabecular dysgenesis and ectropion uveae. Ophthalmology 1985; 92:912–921. 47. Mandal AK. Late-onset unilateral primary developmental glaucoma associated with iridotrabecular dysgenesis, congenital ectropion uveae and thickened corneal nerves: a new neural crest syndrome? Ophthalmic Surg Lasers 1999; 30:567–570. 48. August PS, Niederberger H, Helbig H. Progression of congenital ectropion uveae. Arch Ophthalmol 2003; 121:1511. 49. Cross HE, Maumenee AE. Progressive spontaneous dissolution of the iris. Surv Ophthalmol 1973; 18:186. 50. Cross HE. Ectopia lentis et pupillae. Am J Ophthalmol 1979; 88:381–384. 51. Judisch GF, Martin-Casals A, Hanson JW, Olin WH. Oculodentodigital dysplasia. Four new reports and a literature review. Arch Ophthalmol 1979; 97:878–884. 52. Ozeki H, Shirai S, Ikeda K, Ogura Y. Anomalies associated with AxenfeldRieger syndrome. Graefe’s Arch Clin Exp Ophthalmol 1999; 237:730–734. 53. Asai T, Matsumoto H, Shingu K. Difﬁcult airway management in a baby with Axenfeld-Rieger syndrome. Paediatr Anaesth 1998; 8:444. 54. Bateman JB, Maumenee IH, Sparkes RS. Peters anomaly associated with partial deletion of the long arm of chromosome 11. Am J Ophthalmol 1984; 97:11–15. 55. Townsend WM. Congenital corneal leukomas. 1. Central defect in Descemet’s membrane. Am J Ophthalmol 1974; 77:80–86. 56. Townsend WM, Font RL, Zimmerman LE. Congenital corneal leukomas. 2. Histopathologic ﬁndings in 19 eyes with central defect in Descemet’s membrane. Am J Ophthalmol 1974; 77:192–206. 57. Stone DL, Kenyon KR, Green WR, Ryan SJ. Congenital central corneal leukoma (Peters anomaly). Am J Ophthalmol 1976; 81:173–193. 58. Nakanishi I, Brown SI. The histopathology and ultrastructure of congenital, central corneal opacity (Peters anomaly). Am J Ophthalmol 1971; 72:801–812. 59. Polack FM, Graue EL. Scanning electron microscopy of congenital corneal leukomas (Peters anomaly). Am J Ophthalmol 1979; 88:169–178. 60. Heckenlively J, Kielar R. Congenital perforated cornea in Peters anomaly. Am J Ophthalmol 1979; 88:63–65. 61. Kuper C, Kuwabara T, Stark WJ. The histopathology of Peters anomaly. Am J Ophthalmol 1975; 80:653–660. 62. Ozeki H, Shirai S, Nazaki M, et al. Ocular and systemic features of Peters anomaly. Graefe’s Arch Clin Exp Ophthalmol 2000; 238:833–839.

63. Wolter JR, Haney WP. Histopathology of keratoconus posticus circumscriptus. Arch Ophthalmol 1963; 69:357–362. 64. Yang LL, Lambert SR. Peters anomaly. A synopsis of surgical management and visual outcome. Ophthalmol Clin North Am 2001; 14:467–477. 65. Yang LL, Lambert SR, Lynn MJ, Stulting RD. Surgical management of glaucoma in infants and children with Peters anomaly: long-term structural and functional outcome. Ophthalmology 2004; 111:112–117. 66. Walton DS. Glaucoma in aniridia. In: Ritch R, Shields MB, eds. The secondary glaucomas. CV Mosby Co: St Louis; 1982. 67. Elsas FJ, Maumenee IH, Kenyon KR, Yoder F. Familial aniridia with preserved ocular function. Am J Ophthalmol 1977; 83:718–724. 68. Grove JH, Shaw MW, Bourge G. A family study of aniridia. Arch Ophthalmol 1961; 65:81–84. 69. Hudson AC. Congenital aniridia treated by sclerocorneal trephining. Trans Ophthalmol 1961; 65:81–84. 70. Layman PR, Anderson DR, Flynn JT. Frequent occurrence of hypoplastic optic disc in patients with aniridia. Am J Ophthalmol 1974; 77:513–516. 71. Shaffer RN, Cohen JS. Visual reduction in aniridia. J Ped Ophthalmol 1975; 12:220–222. 72. Shaw MW, Falls HF, Neil JV. Congenital aniridia. Am J Hum Genet 1960; 12:389–415. 73. Neher EM. Aniridia congenita, iridermia. Am J Ophthalmol 1938; 21:293–298. 74. Walton DS. Aniridia with glaucoma. In: Chandler PA, Grant WM, eds. Glaucoma. Lea & Febiger: Philadelphia; 1979:351–354. 75. Pagon AR. Ocular coloboma. Surg Ophthalmol 1981; 25:223–236. 76. Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia with development of glaucoma. Am J Ophthalmol 1974; 18:842–847. 77. David R, MacBeath L, Jenkins T. Aniridia associated with microcornea and subluxated lenses. Br J Ophthalmol 1978; 62:118–121. 78. Brandt JD, Casuso LA, Budenz DL. Markedly increased central corneal thickness: an unrecognized ﬁnding in congenital glaucoma. Am J Ophthalmol 2004; 137:348–350. 79. Chen TC, Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol 1999; 117:1144–1148. 80. Adachi M, Dickens CJ, Hetherington J Jr, et al. Clinical experience of trabeculotomy for the surgical treatment of aniridic glaucoma. Ophthalmology 1997; 104:2121–2125. 81. Mullaney PBB, Selleck C, Al-Awad A, Al-Mesfer S, Zwaan J. Combined trabeculotomy and trabeculectomy as an initial procedure in uncomplicated congenital glaucoma. Arch Ophthalmol 1999; 117:457–460. 82. Wiggins RE Jr, Tomey KF. The results of glaucoma surgery in aniridia. Arch Ophthalmol 1992; 110:503–505. 83. Mandal AK, Prasad K, Naduvilath TJ. Surgical results and complications of mitomycin C-augmented trabeculectomy in refractory developmental glaucoma. Ophthalmic Surg Lasers 1999; 30:473–480. 84. Arroyave CP, Scott IU, Gedde SJ, Parrish RK 2nd, Feuer WJ. Use of glaucoma drainage devices in the management of glaucoma associated with aniridia. Am J Ophthalmol 2003; 135:155–159. 85. Kirwan JF, Shah P, Khaw PT. Diode laser cyclophotocoagulation: role in the management of refractory pediatric glaucomas. Ophthalmology 2002; 109:316–323. 86. Weiss DS, Ritch R. Glaucoma in the phakomatoses. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, Vol. II, Ch 52. CV Mosby: St. Louis; 1989:905–929. 87. Lieberman TW, Podos SM, Hartstein J. Acute glaucoma, ectopia lentis and homocystinuria. Am J Ophthalmol 1966; 61:252–255. 88. Pollard ZF. Secondary angle-closure glaucoma in cicatricial retrolental ﬁbroplasia. Am J Ophthalmol 1980; 89:651–653. 89. Smith J, Shivitz I. Angle-closure glaucoma in adults with cicatricial retinopathy of prematurity. Arch Ophthalmol 1984; 102:371–372. 90. Roy FH, Summit RL, Hiatt RL, Hughes JG. Ocular manifestations of the Rubinstein-Taybi syndrome. Case report and review of the literature. Arch Ophthalmol 1968; 79:272–278.

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Chapter 8 Overview of the management of developmental glaucomas Introduction Overview of clinical management Factors influencing therapeutic decisions Conclusion

Introduction The primary objective in the management of the developmental glaucomas is to normalize and permanently control the intraocular pressure, thereby preventing loss of visual acuity, preserving visual ﬁeld and ocular integrity, and stimulating the development of binocular stereoscopic vision. In 1939, J. Ringland Anderson1 stated that ‘the future of children with hydrophthalmia [primary infantile glaucoma] is bleak... with little hope of preserving sufﬁcient sight to permit the earning of a livelihood.’ Today a much more optimistic outlook has been reached. It is rare to see a neglected patient with a poor outcome (Fig. 8.1). The improved prognosis of the developmental glaucomas is due to accurate and early diagnosis, as well as prompt and effective treatment. Glaucoma in the infant is an uncommon disease, but the impact on the visual development is profound. Any vision during the child’s formative years is worth ﬁghting for, even if it is ultimately lost in severe cases, because appropriate and early therapy of this relatively uncommon condition may improve the child’s visual future. This chapter provides an overview of the management of the developmental glaucomas, and highlights the factors influencing therapeutic decisions in the child with glaucoma.

Overview of clinical management Medical therapy usually provides a supportive role to reduce the intraocular pressure temporarily, to clear the cornea, and to facilitate surgical intervention. Most patients who require long term medical therapy have severe disease that has not responded to surgical therapy. Medical therapy for pediatric glaucomas is described in detail in Chapter 9. Laser therapy has a limited role in the treatment of developmental glaucomas. The effective and deﬁnitive form of treatment of most of the developmental glaucomas is surgical. Primary surgical treatment is usually with goniotomy or trabeculotomy, although combined trabeculotomy and trabeculectomy may be useful in certain populations with a high risk for failure of goniotomy or trabeculotomy (Chapter 10). Some patients will not respond well to initial surgery for developmental glaucoma. As described in Chapter 12, these patients may respond to a variety of surgical treatments, including trabeculectomy with antiﬁbrosis drugs, glaucoma drainage implants, and cyclodestructive procedures.

Factors influencing therapeutic decisions The choice of surgical therapy in the developmental glaucomas is dependent on a variety of factors (Table 8.1). Most important of these is the structural defect2,3 associated with the elevated intraocular pressure. In addition, age, corneal clarity, and associated systemic syndromes can influence the choice of therapy.

Structural defects Isolated trabeculodysgenesis is the hallmark of primary developmental glaucoma. In most instances, abnormal development of the trabecular meshwork increases the resistance

Table 8.1 Factors influencing clinical treatment Structural defects Age Systemic syndromes Corneal clarity Figure 8.1 Untreated congenital glaucoma. Untreated patients are uncommon, and the prognosis of congenital glaucoma has improved with more effective diagnosis and treatment.

Severity of glaucoma Corneal diameter

55

Overview of management to aqueous outflow, which causes the elevated intraocular pressure. This condition is highly responsive to both goniotomy and trabeculotomy ab externo. The classic operation for the treatment of primary infantile glaucoma is Barkan’s goniotomy,4 a procedure which has changed little since its original description. In recent years, however, there has been a trend toward trabeculotomy ab externo.5–7 In iridotrabeculodysgenesis, the success rate for goniotomy and trabeculotomy decreases. When the only iris defect is hypoplasia of the anterior stroma, good response to goniotomy or trabeculotomy has been noted. However, when the iris defect includes abnormal vessels that appear to wander somewhat irregularly across the surface of the iris, then the prognosis is poor. In such cases, multiple surgeries are usually needed. If the angle can be easily visualized, goniotomy may be attempted, but trabeculotomy is probably the better initial procedure of choice. When there are extensive iris structural defects, careful evaluation of the angle is necessary. In aniridia, Grant and Walton8 noted gradual folding up of the peripheral stump of the iris over the trabecular meshwork forming the peripheral anterior synechia that blocks aqueous outflow. They believe this is a common cause of glaucoma in aniridia, and recommend prophylactic goniotomies to prevent the adhesion. Hoskins and associates frequently noted an anterior insertion of iris stroma in patients with aniridia, which is not an acquired process but present at birth. The stroma of the stump of the iris seems to sweep up across the angle. In the presence of this developmental anomaly, we prefer trabeculotomy ab externo for the initial operation when medical therapy fails. In iridocorneotrabeculodysgenesis, the prognosis for surgical treatment is poor. Often medical therapy is unsuccessful, and surgical intervention becomes necessary. Ab externo combined trabeculotomy and trabeculectomy may be useful as the initial operation in these patients to control the intraocular pressure. Angle-closure glaucoma is uncommon in childhood, but is important to recognize when it occurs. The surgical treatments for open-angle glaucoma are not effective for angleclosure glaucoma. Closure of the angle may be secondary to an underlying problem, which should be corrected.

Systemic syndromes In Sturge–Weber syndrome, the glaucoma can be present at birth or appear at anytime from infancy to adulthood. The mechanism of the glaucoma remains controversial9,12 and these patients show varying response to surgical therapy according to their age. When glaucoma is present in infancy, the developmental anomaly that obstructs aqueous outflow may predominate, which resembles the situation in primary congenital glaucoma.9 Many surgeons prefer goniotomy or trabeculotomy as the operation of choice but report that the rate of success is consistently lower than that with primary congenital glaucoma.10,11 When glaucoma in Sturge–Weber syndrome has its onset in later life, it is thought to be primarily due to elevated episcleral venous pressure.9 The angle defect is less severe and is sometimes minimal. In such patients, medical therapy should be tried ﬁrst. If medical therapy fails, some surgeons feel that ﬁltering procedures, such as trabeculectomy, should be performed on these eyes.12–14 We often use a technique combining ab externo trabeculotomy and trabeculectomy in such cases. The trabeculotomy is performed to remove the possible obstruction to aqueous outflow by a congenital angle deformity, while the trabeculectomy is included to bypass the episcleral venous system. In other words, the combined procedure may address both possible mechanisms of glaucoma association in this disease.15 There may be a rapid accumulation of a massive amount of suprachoroidal fluid during the operative procedure (Fig. 8.2).11,14 This will produce flattening of the anterior chamber, hardening of the globe, and difﬁculty in repositing a prolapsed iris when the sclerotomy is made. After the iridectomy is done, it may be difﬁcult to reposit ciliary processes that rotate anteriorly into the sclerostomy, and vitreous may be lost. These complications can be avoided or minimized if, before entering the anterior chamber, two posterior radial sclerotomies or a triangular sclerotomy are made in the inferior quadrants of the globe. This enables the suprachoroidal effusion to drain out of the eye as it forms.

Age The age of the child at the onset of glaucoma is also a factor in choosing the appropriate therapy. In general, children under the age of 3 years are best treated surgically. Those with isolated trabeculodysgenesis respond well to both goniotomy and trabeculotomy ab externo. It has been observed that goniotomy is less successful after the age of 3 years, whereas trabeculotomy may be successful until later in life. Children over 3 years of age deserve a trial of medical therapy unless the speciﬁc defect of trabeculodysgenesis is seen (including an anterior insertion of the iris, a thickened trabeculum, or a wrapround type of anterior iris stromal insertion). Such patients may be treated with trabeculotomy ab externo.

56

Figure 8.2 Choroidal effusion during the immediate postoperative period in a patient with Sturge–Weber syndrome.

Systemic syndromes To help avoid the complications of conventional glaucoma surgery in eyes with increased episcleral venous pressure, ﬁltration techniques that do not require entry into the anterior chamber have been recommended by some surgeons. These include sinusotomy16 and non-penetrating trabeculectomy with or without Nd:YAG laser trabeculotomy.16,17 Oculocerebrorenal syndrome of Lowe is a rare syndrome, which may be associated with glaucoma and trabeculodysgenesis.18 Hemorrhage may accompany surgery and, therefore, medical therapy should be tried initially. The success of surgery is reduced compared with the success for primary developmental glaucoma. In homocystinuria, secondary glaucoma associated with angle closure may occur, due to subluxation of the lens. Laser or surgical iridotomy or lens removal are surgical options in this situation. Intravascular thrombosis has been reported with anesthesia in patients with homocysteinuria.19 In trisomy 13, congenital glaucoma resulting from poor differentiation of the angle structures has been reported.20 However, most of these patients die within the ﬁrst few weeks of life, with only 18% of patients surviving the ﬁrst year. Thus, in this syndrome and in others that have a high mortality rate, surgical intervention is warranted only in eyes that have a good prognosis and patients in whom longevity is likely to be good. Consultation with the pediatrician is useful in deciding management for these patients. In chronic childhood uveitis, goniotomy is a useful initial surgical procedure. Freedman and coworkers described the efﬁcacy of goniotomy in 12 patients with childhood uveitic glaucoma and found an overall success of 75% with a mean follow-up of 32 months.21 Ho and coworkers reported experience with 54 goniotomies performed in 40 eyes of 31 patients, the majority with a diagnosis of juvenile rheumatoid arthritisassociated uveitis.22 Overall surgical success was achieved in 29 eyes (72%). Surgical outcome was adversely affected by increased age, peripheral anterior synechiae, prior surgeries, and aphakia.

Figure 8.3 Corneal edema due to elevated intraocular pressure in a patient with aniridia. The opacity of the cornea is associated with a poor gonioscopic view of the angle, which precludes goniotomy.

until they were a week or so of age to reduce anesthetic risk. With current anesthetic techniques, surgery can be safely performed on the second or third day of life. We feel that early surgery has salvaged more eyes than with delayed surgery.

Corneal diameter Some authors have had the impression that corneal enlargement was a poor prognostic factor in trabeculotomy.25 However, this has not been the experience of Luntz and Livingston in a prospective study of 86 treated eyes.23,26 Quigley27 reported a success rate of 67% in eyes with corneal diameter greater than 14 mm compared to 100% success in eyes less than 14 mm. However, McPherson and McFarland28 noted that corneal diameter had little effect on the ﬁnal outcome of the external trabeculotomy. The success of goniotomy is decreased in eyes with signiﬁcant buphthalmos (Fig. 8.4). Barkan29 felt that eyes with corneal diameters greater that 15 mm were not suitable for goniotomy. Similarly, Robertson30 reported 13 of 15 successes in non-buphthalmic eyes compared with only 3 of 10

Corneal clarity In situations where corneal clouding prevents adequate visualization of the trabecular meshwork by gonioscopy, trabeculotomy ab externo has to be performed in children with developmental glaucoma as the initial surgical procedure (Fig. 8.3).23,24

Severity of glaucoma In advanced cases of developmental glaucomas, initial goniotomy or trabeculotomy may be tried, but has a high failure rate. In this situation, combined trabeculotomy and trabeculectomy may offer a higher success rate than goniotomy or trabeculotomy. If the initial surgical procedure fails, it may be necessary to perform trabeculectomy with an adjunctive antiﬁbrosis drug or glaucoma drainage implant. Patients who appeared at birth with bilateral cloudy corneas and severe glaucoma often had surgery delayed

Figure 8.4 Buphthalmos in a child with bilateral congenital glaucoma. Severe corneal enlargement and buphthalmos is associated with decreased success of goniotomy and may be associated with increased risk of surgical complications.

57

Overview of management successes in buphthalmic eyes. In patients with a signiﬁcant increase in corneal diameter, goniotomy is technically difﬁcult to perform and the initial procedure of choice should be trabeculotomy or ab externo combined trabeculotomy and trabeculectomy. Our impression has been that complications may occur with increased frequency in eyes with severe corneal enlargement and buphthalmos. Additional precautions to avoid complications improve safety during the postoperative period. These precautions include tightly sutured trabeculectomy flap and two stage glaucoma drainage device implantation, in order to minimize postoperative hypotony.

Conclusion Surgical therapy is the most effective and deﬁnitive form of treatment for the developmental glaucomas. The choice of surgical therapy is influenced by a variety of factors, including the structural defect, age of the patient, corneal clarity, and associated systemic syndromes. Consideration of these factors may guide the clinician toward more effective treatment strategies.

References 1. Anderson JR. Hydrophthalmia or congenital glaucoma. Cambridge University Press: London; 1939:14–16. 2. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classiﬁcation of the developmental glaucomas. Arch Ophthalmol 1984; 102:133–136. 3. Hoskins HD Jr, et al. Developmental glaucoma: diagnosis and classiﬁcation. In: The New Orleans Academy of Ophthalmology Symposium on Glaucoma. CV Mosby: St. Louis; 1981. 4. Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217–221. 5. Burian HM. A case of Marfan’s syndrome with bilateral glaucoma with a description of a new type of operation for developmental glaucoma. Am J Ophthalmol 1960; 50:1187–1192. 6. Smith R. A new technique for opening the canal of Schlemm. Br J Ophthalmol 1960; 44:370–373. 7. Burian HM, Allen L. Trabeculotomy ab externo; a new glaucoma operation: technique and results of experimental surgery. Am J Ophthalmol 1962; 53:19–26. 8. Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia, with development of glaucoma. Am J Ophthalmol 1974; 78:842–847.

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9. Weiss DL. Dual origin of glaucoma in encephalotrigeminal hemangiomatosis. Trans Ophthalmol Soc UK 1973; 93:477–491. 10. Barkan O. Goniotomy for glaucoma associated with nevus flammeus. Am J Ophthalmol 1957; 43:545–549. 11. Christensen GR, Records RE. Glaucoma and expulsive hemorrhage mechanism in the Sturge-Weber syndrome. Ophthalmology 1979; 86:1360–1366. 12. Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Ophthalmology 1978; 85:276–286. 13. Keverline DO, Hills DA. Trabeculectomy for adolescent glaucoma in Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus 1977; 13:144–148. 14. Bellows AR, Chylark LT, Epstein DL, et al. Choroidal effusion during glaucoma surgery in patients with prominent episcleral vessels. Arch Ophthalmol 1979; 97:493–497. 15. Board RJ, Shields MB. Combined trabeculotomy-trabeculectomy for the management of glaucoma associated with Sturge-Weber syndrome. Ophthalmic Surg 1981; 12:813–817. 16. Krasnov MM. Microsurgery of the glaucomas. CV Mosby: St Louis; 1979. 17. Zimmerman TJ, Kooner KS, Ford VJ, et al. Trabeculectomy vs nonpenetrating trabeculectomy: a retrospective study of two procedures in phakic patients with glaucoma. Ophthalmic Surg 1984; 15:734–740. 18. Curtin VT, Joyce EE, Ballin N. Ocular pathology in the oculo-cerebro-renal syndrome of Lowe. Am J Ophthalmol 1967; 64(3); Suppl:533–543. 19. Komrower GM, Wilson VK. Homocystinuria. Proc R Soc Med 1963; 56:996–997. 20. Lichter PR, Schmickel RD. Posterior vortex vein and congenital glaucoma in a patient with trisomy-13 syndrome. Am J Ophthalmol 1975; 80:939–942. 21. Freedman SF, Rodriguez-Rosa RE, Rojas MC, Enyedi LB. Goniotomy for glaucoma secondary to chronic childhood uveitis. Am J Ophthalmol 2002; 133:617–621. 22. Ho CL, Wong EYM, Walton DS. Goniosurgery for glaucoma complicating chronic childhood uveitis. Arch Ophthalmol 2004; 122:838–844. 23. Luntz MH, Livingston DG. Trabeculotomy ab externo and trabeculectomy in congenital and adult-onset glaucoma. Am J Ophthalmol 1977; 83:174–179. 24. Hoskins HD, Shaffer RN, Hetherington J. Goniotomy vs trabeculotomy. J Pediatr Ophthalmol Strabismus 1984; 21:153–158. 25. Gregerson E, Kessing SVV. Congenital glaucoma before and after the introduction of microsurgery. Results of ‘Macro-surgery’ 1943–1963 and of microsurgery (Trabeculotomy/ectomy) 1970–1974. Acta Ophthalmol 1977; 55:422–430. 26. Luntz MH. Primary buphthalmos (infantile glaucoma) treated by trabeculotomy ab externo. S Afr Arch Ophthalmol 1974; 2:319–334. 27. Quigley HA. Childhood glaucoma: results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–225. 28. McPherson SD, McFarland D. External trabeculotomy for developmental glaucoma. Ophthalmology 1980; 87:302–305. 29. Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 1948; 32:701–728. 30. Robertson EN Jr. Therapy of congenital glaucoma. AMA Arch Ophthalmol 1955; 54:55–58.

Chapter 9 Medical therapy of pediatric glaucoma Introduction Beta-blockers Carbonic anhydrase inhibitors Prostaglandin-related drugs Alpha-2 agonists Other adrenergic agonists Cholinergic drugs Osmotic drugs Conclusion

Introduction In pediatric patients, medical therapy is usually accorded a supportive role to reduce the intraocular pressure temporarily, to clear the cornea, and to facilitate surgical intervention. Deﬁnitive treatment of primary congenital glaucoma is usually accomplished with surgical intervention. Most patients who require long-term medical therapy have severe disease that has not responded to surgical therapy. Although regulatory agencies worldwide usually do not include children in antiglaucoma drug approval studies, clinicians have found these medications useful in children with elevated intraocular pressure (Table 9.1). Some children with congenital glaucoma and elevated intraocular pressure respond to medical therapy. In 161 eyes with congenital glaucoma, medical therapy alone reduced the intraocular pressure to less than 21 mmHg in 12% of eyes in the short-term and 10% of eyes in the long term.1 When

Table 9.1 Glaucoma medications in common usage in pediatric patients Beta-blockers Timolol solution 0.25% (qd, bid) Timolol gel-forming solution 0.25% (qd) Levobunolol 0.25% (qd, bid) Betaxolol 0.25% (qd, bid) Carbonic anhydrase inhibitors Dorzolamide 2% (bid, tid) Brinzolamide 1% (bid, tid) Acetazolamide elixir 5–15 mg/kg/day in divided doses (bid, tid) Prostaglandin-related drugs Latanoprost 0.005% (qd) Travoprost 0.004% (qd) Bimatoprost 0.03% (qd)

contemplating medical therapy in children, clinicians should evaluate the risks and beneﬁts of the individual medications, use the minimum dosages required to achieve a therapeutic beneﬁt, and monitor children for ocular and systemic side effects.2,3

Beta-blockers The response to adjunctive treatment with timolol has been studied in patients with a variety of pediatric glaucomas. In 34 patients with childhood glaucoma, timolol was added to other medical therapy, causing a deﬁnite improvement in 29%, a modest or equivocal improvement in 32%, and no improvement in 39%.4 In 38 eyes treated with timolol as adjunctive therapy, 37% of eyes were controlled at 22 mmHg or less.5 In 89 eyes with various types of pediatric glaucoma, an intraocular pressure lowering effect was observed only in 20% of eyes.6 Similarly, in 100 eyes with childhood glaucoma treated with timolol, 31% experienced a reduction of intraocular pressure (Fig. 9.1).7 After the initial response, increased an intraocular pressure over time may occur.5 Plasma timolol levels in children after treatment with 0.25% timolol greatly exceed those in adults after instillation of 0.5% timolol, especially in infants.8 Increased plasma timolol levels in children are explained by the volume of distribution of the drug, which is much smaller in children compared with adults. Higher plasma levels of drug would be expected to be associated with an increased risk of systemic side effects in children, especially young children, compared with adults. In children over 5 years old, reduction in resting pulse rates have been identiﬁed and are comparable to those observed in adults.4 Side effects have occurred in 4% to 13% of children,5,6 and timolol therapy has been discontinued in 3% to 7% of patients.4,5 Serious adverse events such as apnea, have been reported, especially in younger children with smaller body mass and blood volume for drug distribution compared with adults.9–11 Provocation of asthma may occur with topical timolol treatment. It is not known whether betaxolol, a selective beta-blocker, reduces the risk of pulmonary side effects in children compared with timolol. The effects of long-term use of topical beta blockers in children are not reported. Timolol in 0.25% and 0.5% solutions may be used cautiously in young glaucoma patients. The drug should be used with extreme caution in neonates, due to the possibility of apnea and other systemic side effects. A detailed pediatric examination should precede the use of this drug, to elicit the 59

Medical therapy of pediatric glaucoma

A

A

35 30 IOP (mmHg)

Additional treatment required

No added treatment

20

*

*

15 10 5

0

20

40 Percent Eyes

60

0

80

Baseline

B

Acetazolamide

Dorzolamide

> 10 1 to 10

-1 to -10 < -10 0

10

20 30 Percent Eyes

40

50

Figure 9.1 Timolol in pediatric glaucomas. (A) In a series of 100 eyes treated with timolol maleate, the majority (60%) required additional surgery or medications. (B) The change from baseline intraocular pressure (IOP) in the 40 eyes receiving timolol therapy without additional surgery or medications. Of the 40 eyes that received timolol therapy without additional surgery or medications, 31 (78%) demonstrated reduced IOP after timolol treatment. (Adapted with permission from Hoskins HD Jr, Hetherington J Jr, Magee SD, Naykhin R, Migliazzo CV. Clinical experience with timolol in childhood glaucoma. Arch Ophthalmol 1985; 103:1163–1165. Copyright © (1985) American Medical Association. All rights reserved.)

presence of systemic abnormalities such as bronchial asthma and cardiac disease. In these cases, beta blockers are contraindicated. Use of 0.25% timolol rather than 0.5% timolol is strongly recommended in order to minimize the risk of side effects. Once daily dosing with timolol 0.25% in gel-forming solution may help simplify medical regimens.

Carbonic anhydrase inhibitors Systemic carbonic anhydrase inhibitors would be expected to have similar side effects in children compared with adults. In addition, growth suppression in children has been associated with oral acetazolamide therapy,12 and infants may experience a severe metabolic acidosis.13 Side effects due to systemic carbonic anhydrase inhibitors in infants and young children are not commonly reported, although these patients may not verbalize these side effects to parents or health care providers. Oral administration of acetazolamide suspension in a dosage of 10 (range 5–15) mg/kg/day given in divided doses (three times daily) is safe and well tolerated by children, lowers intraocular pressure, and may reduce corneal edema as a prelude to surgery.14,15

Dorzolamide (% Decrease IOP)

Change IOP (mmHg)

B

No Change

60

25

55 45 35 25 15 5 -5

0

10

20 30 40 50 Acetazolamide (% Decrease IOP)

60

Figure 9.2 Carbonic anhydrase inhibitors in pediatric patients treated with beta blocker at baseline. (A) Intraocular pressure (IOP) was signiﬁcantly reduced from baseline (on topical beta blocker alone) after addition of acetazolamide (mean ± standard deviation decrease of 35.7 ± 15.6%) or dorzolamide (27.4 ± 17.1%). Y error bars indicate standard error of mean (SEM). Asterisk indicates P < 0.01 compared with baseline. (B) Correlation between efficacy of oral and topical carbonic anhydrase inhibitor therapy. The percentage reduction of intraocular pressure (IOP) in 8 eyes on topical beta-blocker therapy was similar after addition of acetazolamide (oral) or dorzolamide (topical) treatment (r = 0.94). (Adapted with permission from Portellos M, Buckley EG, Freedman SF. Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. J AAPOS 1998; 2:43–47.)

Topical versus oral carbonic anhydrase inhibitor therapy has been evaluated for pediatric glaucoma in a crossover design study.16 The mean intraocular pressure was reduced by 36% and 27% compared with baseline after treatment with oral acetazolamide and topical dorzolamide, respectively (Fig. 9.2). All eyes showed an increase in intraocular pressure when switched from acetazolamide to dorzolamide, with a mean increase of 3.7 mmHg. Although not as effective as acetazolamide in this group of patients, topical dorzolamide caused a signiﬁcant reduction of intraocular pressure and was well tolerated. At present, topical carbonic anhydrase inhibitors are more commonly prescribed compared with systemic carbonic anhydrase inhibitors. Many clinicians recommend twice daily dosing, in order to minimize discomfort to the parent and child associated with three times daily dosing. For older children, the ﬁxed combination of dorzolamide with timolol

Alpha-2 agonists may simplify medical regimens, reducing the number of drops instilled per day.

A prostaglandin-related drug, speciﬁcally latanoprost, has been evaluated in studies of a variety of glaucoma diagnoses, including glaucoma associated with Sturge–Weber syndrome.17–21 In 31 eyes with a variety of glaucoma diagnoses, 6 (19%) of treated eyes responded with a decrease of intraocular pressure averaging 8.5 mmHg (34% reduction), whereas the majority of eyes were nonresponders (Fig. 9.3).17 Responders were more likely to have juvenile-onset openangle glaucoma and to be older than nonresponders. The drug was well tolerated in this short-term study. In glaucoma associated with Sturge–Weber syndrome, 17% to 28% of eyes treated with latanoprost responded with a reduction of intraocular pressure.18,19 Increased episcleral venous engorgement was noted, and one patient (6%) discontinued therapy because of intolerable conjunctival hyperemia.19

Nonresponders Responders

N=25

B 35

IOP (mmHg)

30

Nonresponders Responders

0.4 0.2 0.0

0

1

2

3 4 Follow-up (months)

5

6

Figure 9.4 Kaplan–Meier survival curve showing response to latanoprost in patients with Sturge–Weber syndrome and glaucoma. A successful response to latanoprost was defined as a reduction of intraocular pressure of at least 20% from baseline without additional medical or surgical therapy and no adverse events related to latanoprost therapy. Medical therapy can be effective in patients with Sturge–Weber syndrome, but patients often require additional therapy. (Reproduced with permission from Altuna JC, Greenfield DS, Wand M, et al. Latanoprost in glaucoma associated with Sturge–Weber syndrome: benefits and side effects. J Glaucoma 1999; 8:199–203.)

Alpha-2 agonists

25 20 * 15 10 Baseline

0.6

Although a declining success rate occurs over time, half of the patients were controlled at 1 year follow-up following a trial of latanoprost as adjunctive therapy (Fig. 9.4).20 Although the majority of children do not respond well to latanoprost, some children may have a signiﬁcant ocular hypotensive effect with latanoprost treatment.21 Side effects are infrequent and mild, and the dosage schedule is convenient. Parents and patients should be advised about the possibility of local side effects, including iris pigmentation change, eyelash growth, and hyperemia. When medical therapy prior to surgery or other short-term medical therapy is planned, these local side effects are generally not a problem. However, the prevalence and types of side effects associated with long-term therapy are not known.

A

N=6

0.8 Success

Prostaglandin-related drugs

1.0

Latanoprost

Figure 9.3 Latanoprost in pediatric glaucomas. (A) In a series of 31 eyes, the majority of children (25) were non-responders (<15% decrease of intraocular pressure). Medical therapy using any particular drug is usually effective in a minority of pediatric glaucoma patients. (B) In 31 eyes, latanoprost was effective in 6 responders (*15% decrease IOP). The average IOP reduction in latanoprost responders was 8.5 ± 3.6 mmHg (34.0 ± 10.9%, asterisk denotes P = 0.002). Y error bars indicate standard deviation. (Adapted with permission from Enyedi LB, Freedman SF, Buckley EG. The effectiveness of latanoprost for the treatment of pediatric glaucoma. J AAPOS 1999; 3:33–39.)

Several non-comparative case series have described the use of brimonidine in pediatric glaucoma patients, whereas the use of apraclonidine has not been described in pediatric patients. In 30 patients with a mean age of 10 years, brimonidine treatment was associated with a mean reduction of intraocular pressure by 7%.22 Two young children (ages 2 and 4 years) were transiently unarousable after administration of brimonidine, and ﬁve other children experienced extreme fatigue.22 In 23 patients with a mean age of 8 years, 18% had systemic adverse effects sufﬁcient to necessitate stopping the drug.23 Four pediatric patients have been reported to develop somnolence after treatment with brimonidine.24 A 1-month-old infant developed recurrent episodes of ‘coma’ (unresponsiveness, hypotension, hypotonia, hypothermia, and bradycardia) following treatment with brimonidine.25 Alpha-2 agonists are less commonly used in pediatric patients compared with adult patients. The potential for central nervous system mediated side effects is greater with lipophilic drugs (e.g., brimonidine) compared with more hydrophilic drugs that are less likely to cross the blood–brain 61

Medical therapy of pediatric glaucoma barrier (e.g., apraclonidine). Iopidine may help to minimize intraoperative hyphema in the setting of goniotomy.26 Brimonidine should be used with caution in pediatric patients, and only used in older children.

Other adrenergic agonists Although uncommonly prescribed at present, epinephrine (1%) has been used in children.27 Lack of efﬁcacy and the potential for systemic toxicity (tachyarrythmia, hypertension) limit the use of this drug. A reactive conjunctival hyperemia may occur following the initial vasoconstriction. After prolonged use, melanin-like adrenochrome deposits may be noted in the conjunctiva, and occasionally in the cornea. Dipivefrin hydrochloride 0.1%, a prodrug of epinephrine, may also be used in children. Side effects may be attenuated compared with epinephrine, except for a high frequency of local allergic reactions. The drops are administered every 12–24 hours. In aphakic or pseudophakic pediatric patients, these drugs should be avoided due to the risk of cystoid macular edema.

Cholinergic drugs Although miotic drugs increase the facility of aqueous outflow in normal persons as well as glaucoma patients, and thus lower intraocular pressure, these drugs are probably not as effective in developmental glaucoma because of the abnormal insertion of ciliary muscle into the trabecular meshwork. In pediatric patients, the use of pilocarpine (2% concentration, topically applied every six to eight hours) is limited.14 However, these drugs may be helpful in aphakic or pseudophakic children with elevated intraocular pressure. Also, cholinergic drugs may be useful in achieving miosis before and after goniotomy.26 The induced myopia caused by the miotics can produce disabling visual difﬁculties. A slow-release pilocarpine membrane delivery system (Ocusert), currently not available, was helpful in some young patients,28 although sudden release of pilocarpine (burst effect) rarely induced myopic spasms. Ciliary spasm and angle-closure glaucoma have been precipitated by the use of phospholine iodide for esotropia in a child.29 The long-acting anticholinesterase drugs are not readily available, are associated with serious adverse effects, and offer no advantages over pilocarpine for use in children. Echothiophate iodide (phospholine iodide), which is instilled every 12 to 24 hours, is a potent and relatively irreversible inhibitor of cholinesterase. The systemic absorption of anticholinesterase agents can signiﬁcantly reduce the serum cholinesterase and pseudocholinesterase levels. Affected patients, especially children, may show signs of weakness, diarrhea, nausea, vomiting, salivation, decreased heart rate, and other evidence of parasympathetic nervous system stimulation. This becomes particularly dangerous when surgery is contemplated, since succinylcholine is commonly employed as a muscle relaxant during general anesthesia. This drug is normally promptly hydrolyzed by cholinesterase at the 62

nerve endings. However, when the cholinesterase level is low, prolonged apnea can result.

Osmotic drugs Glycerol or glycerine is administered in a dose of 0.75–1.5 g/ kg body weight, orally, in a 50% solution.30 The very sweet taste may be partially masked by chilling the solution over ice and by using fruit juice (lemon or orange) or flavored water as a diluent. This drug is rarely used in the treatment of the developmental glaucomas. Mannitol (20% solution) is administered intravenously in a dose of 0.5–1.5 g/kg body weight, at approximately 60 drops per minute. A rapid fall in pressure occurs in 20–30 min and lasts for 4–10 hours. Mannitol may be administered to reduce the intraocular pressure before surgery in patients with developmental glaucomas with intraocular pressure that remains very high even with standard medical therapy.

Conclusion Medical therapy for pediatric glaucoma patients is often administered to reduce the intraocular pressure temporarily, to clear the cornea, and to facilitate surgical intervention. Most patients who require long-term medical therapy have severe disease that has not responded to surgical therapy. Some patients with elevated intraocular pressure, however, may respond to therapy with various medications. Prior to initiating medical therapy, clinicians should carefully consider the potential for side effects. When using topical glaucoma medications, children may be at increased risk of systemic side effects compared with adults, due to reduced body mass and blood volume for drug distribution.

References 1. Turach ME, Aktan G, Idil A. Medical and surgical aspects of congenital glaucoma. Acta Ophthalmol Scand 1995; 73:261–263. 2. Wallace DK, Steinkuller PG. Ocular medications in children. Clin Pediatr 1998; 37:645–652. 3. Palmer EA. How safe are ocular drugs in pediatrics? Ophthalmology 1986; 93:1038–1040. 4. Boger WP 3rd, Walton DS. Timolol in uncontrolled childhood glaucomas. Ophthalmology 1981; 88:253–258. 5. McMahon CD, Hetherington J Jr, Hoskins HD Jr, Shaffer RN. Timolol and pediatric glaucomas. Ophthalmology 1981; 88:249–252. 6. Zimmerman TJ, Kooner KS, Morgan KS. Safety and efﬁcacy of timolol in pediatric glaucoma. Surv Ophthalmol 1983; 28 (Suppl):262–264. 7. Hoskins HD Jr, Hetherington J Jr, Magee SD, Naykhin R, Migliazzo CV. Clinical experience with timolol in childhood glaucoma. Arch Ophthalmol 1985; 103:1163–1165. 8. Passo MS, Palmer EA, Van Buskirk EM. Plasma timolol in glaucoma patients. Ophthalmology 1984; 91:1361–1363. 9. Burnstine RA, Felton JL, Ginther WH. Cardiorespiratory reaction to timolol maleate in a pediatric patient: a case report. Ann Ophthalmol 1982; 14:905–906. 10. Bailey PL. Timolol and postoperative apnea in neonates and young infants. Anesthesiology 1984; 61:622. 11. Olsen RJ, Bromberg BB, Zimmerman TJ. Apneic spells associated with timolol therapy in a neonate. Am J Ophthalmol 1979; 88:120–122. 12. Futagi Y, Otani K, Abe J. Growth suppression in children receiving acetazolamide with antiepileptic drugs. Pediatr Neurol 1996; 15:323–326. 13. Ritch R. Special therapeutic situations. In: Netland PA, Allen RC, eds. Glaucoma medical therapy: principles and management. San Francisco: American Academy of Ophthalmology; 1999:193–211.

References 14. Hass J. Principles and problems of therapy in congenital glaucoma. Invest Ophthalmol 1968; 7:140–146. 15. Shaffer RN. New concepts in infant glaucoma. Trans Ophthalmol Soc UK 1967; 87:581–585. 16. Portellos M, Buckley EG, Freedman SF. Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. J AAPOS 1998; 2:43–47. 17. Enyedi LB, Freedman SF, Buckley EG. The effectiveness of latanoprost for the treatment of pediatric glaucoma. J AAPOS 1999; 3:33–39. 18. Yang CB, Freedman SF, Myers JS, et al. Use of latanoprost in the treatment of glaucoma associated with Sturge-Weber syndrome. Am J Ophthalmol 1998; 126:600–602. 19. Altuna JC, Greenﬁeld DS, Wand M, et al. Latanoprost in glaucoma associated with Sturge-Weber syndrome: beneﬁts and side-effects. J Glaucoma 1999; 8:199–203. 20. Ong T, Chia A, Nischal KK. Latanoprost in port wine stain related paediatric glaucoma. Br J Ophthalmol 2003; 87:1091–1093. 21. Enyedi LB, Freedman SF. Latanoprost for the treatment of pediatric glaucoma. Surv Ophthalmol 2002; 47 (Suppl):S129–S132. 22. Enyedi LB, Freedman SF. Safety and efﬁcacy of brimonidine in children with glaucoma. J AAPOS 2001; 5:281–284.

23. Bowman RJ, Cope J, Nischal KK. Ocular and systemic side effects of brimonidine 0.2% eye drops (Alphagan) in children. Eye 2004; 18:24–26. 24. Levy Y, Zadok D. Systemic side effects of ophthalmic drops. Clin Pediatr 2004; 43:99–101. 25. Berlin RJ, Lee UT, Samples JR, et al. Ophthalmic drops causing coma in an infant. J Pediatr 2001; 138:441–443. 26. Freedman SF. Medical and surgical treatments for childhood glaucomas. In: Epstein DL, Allingham RR, Schuman JS, eds. Chandler and Grant’s glaucoma, 4th edn. Williams & Wilkins: Baltimore, MD; 1997. 27. Raab EL. Congenital glaucoma. Persp Ophthalmol 1978; 2:35–41. 28. Pollack IP, Quigley HA, Harbin TS. The Ocusert pilocarpine system: advantages and disadvantages. South Med J 1976; 69:1296–1298. 29. Jones DE, Watson DM. Angle-closure glaucoma precipitated by the use of phospholine iodide for esotropia in child. Br J Ophthalmol 1967; 51:783–785. 30. Netland PA, Kolker AE. Osmotic drugs. In: Netland PA, Allen RC, eds. Glaucoma medical therapy: principles and management. American Academy of Ophthalmology: San Francisco, CA; 1999:133–147.

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Chapter 10 Initial surgical treatment of congenital glaucoma

Goniotomy

goniotomy knife (Fig. 10.1). A variety of gonioscopy lenses are available for goniotomy, but the most popular and widely used one is the Swan–Jacob lens. It has a metal handle attached to the gonioscopy lens with a convex anterior surface, allowing observation of the angle with the microscope or with loupes. It does not require a viscous fluid space between the lens and the cornea because its corneal contact curvature is flatter than that of the cornea. The lens is small and permits insertion of the goniotomy knife at the limbus without obstruction by the lens. An ideal goniotomy knife should be sharp on both sides to allow it to cut either direction, and it should have a sharp point for entering the trabecular meshwork. The average blade width should be 1–1.5 mm, and the paracentesis incision ideally should not leak after the withdrawal of the knife. The blade is joined to a handle by a tapered shaft, to ﬁll the paracentesis opening and prevent loss of aqueous with subsequent collapse of the anterior chamber when the shaft is inserted into the eye. The shaft and blade also should be slightly longer than the diameter of the anterior chamber. Some goniotomy knives have a ﬁne metal cannula attached to the handle and to a tube running to a reservoir ﬁlled with balanced salt solution, which is infused during the operation to maintain a deep anterior chamber. Both the Barraquer knife and Worst knife fulﬁll all the above criteria and both are equally popular. A Swan spade or a long needle also may be used to perform goniotomy. Visualization of the anterior chamber angle can be achieved with various illumination and magniﬁcation techniques. The procedure can be performed with a headlamp and surgical loupes. The headlamp may be a conventional surgical headlamp or, alternatively, the surgeon may use the light source on an indirect ophthalmoscope. It is possible to use

After the introduction of clinical gonioscopy, Otto Barkan (1936) modiﬁed de Vincentis’ operation (1892) by using a specially designed glass contact lens to visualize the angle structures while using a knife to create an internal cleft in trabecular tissue. He called the operation ‘goniotomy.’1–8 The objective of goniotomy is to remove obstructing tissue that causes resistance to aqueous flow, thereby restoring the access of aqueous to Schlemm’s canal and maintaining the physiologic direction of outflow. Clinical and experimental evidence support the belief that an improved facility of outflow after goniotomy is responsible for the lowering of intraocular pressure.9 In order to perform this surgery, special equipment is required, including a lens for gonioscopic surgery and a

Figure 10.1 Instruments for goniotomy. Swan–Jacob lens (top) and Swan blade (bottom).

Introduction Goniotomy Trabeculotomy ab externo Primary trabeculectomy Ab externo combined trabeculotomy and trabeculectomy Long-term follow-up and prognosis Conclusion

Introduction Early surgical intervention is of prime importance in the management of patients with developmental glaucoma. In some areas of the world, such as the United States, patients may have only mild or moderate corneal edema at referral for treatment. These patients may be candidates for goniotomy, which has a high success rate in Western populations. In other areas of the world, such as India or the Middle East, nearly all patients present with corneal clouding, and goniotomy is technically impossible. In these areas, external trabeculotomy is the initial procedure of choice. When initial trabeculotomy has a poor success rate, trabeculotomy may be combined with trabeculectomy. Another important consideration is that, although most patients have symptoms suggestive of congenital glaucoma at birth or within 6 months of birth, patients often present late due to various nonmedical factors. In such advanced cases, we prefer to perform ab externo combined trabeculotomy and trabeculectomy, which offers the best hope of success.

65

Initial surgical treatment the conventional ophthalmic operating microscope by positioning the patient with a view of the anterior chamber angle. The system most commonly used by the authors at this time is an operating microscope, which allows confocal viewing of the anterior chamber angle and can be adjusted to any viewing position without moving the patient. After induction of general anesthesia, the eye is prepped and draped in the usual manner for the surgical procedure. The Swan–Jacob goniotomy lens is placed on the cornea. For nasal goniotomy, the lens is placed on the cornea with approximately 2 mm of temporal cornea remaining exposed. The locking ﬁxation forceps are placed by the assistant on the vertical recti for a goniotomy performed nasally or temporally. Alternatively, the locking forceps are placed on the horizontal recti for a procedure done inferiorly or superiorly. A paracentesis is performed with a sharp blade, or the goniotomy knife itself is used to enter the anterior chamber. The knife enters the anterior chamber through peripheral clear cornea, approximately 1 mm inside the corneolimbal junction, at the previously selected site. Once in the anterior chamber, the knife is guided parallel to the iris, away from the pupil, toward the trabecular meshwork (Fig. 10.2). The tip of the knife is engaged slightly anterior to the middle of the trabecular meshwork. With the operating microscope, the tip of the knife can be seen to indent the trabecular meshwork before it is cut by circumferential movement of the knife until comfortable visualization of the tissue is no longer possible. During the goniotomy, the tip of the knife should remain in a somewhat superﬁcial position, cutting at the same depth along the incision. When the knife is at optimum depth, there is little or no perceptible tactile sensation of cutting trabecular tissue. If a coarse, grating sensation is felt, the knife is probably positioned too deep. As the incision proceeds, a white line develops behind the blade, the iris falls posteriorly, and the angle deepens. Great care should be taken to avoid touching the iris with the knife edge or damaging the lens. The incision can encompass at least 110 degrees with a maximum sweep. By rotation of the globe by the assistant surgeon, approximately 4 to 6 clock hours of meshwork can be incised.

Schwalbe's line

A

Once the incision has been completed, the blade is withdrawn fairly rapidly taking care not to strike the corneal endothelium, iris, or lens. If the wound leaks, a single 10–0 nylon suture can be used to close the incision site. A moderate amount of bleeding following the surgery is typical and perhaps even a favorable sign indicating that communication has been created to the canal of Schlemm.6,10–16 This bleeding is innocuous and usually rapidly clears following surgery. The whole procedure from the ﬁrst grasping of the muscles by the assistant to the completion of suturing takes approximately 8 to 10 minutes. A drop of an antibiotic– corticosteroid preparation is instilled into the conjunctival sac and a patch and shield are applied to the eye. The following day the patch can be removed. Topical antibiotic– steroid drops are continued until the anterior chamber reaction resolves. The 10–0 nylon suture may be removed approximately 4–6 weeks after surgery. The reported results of goniotomy surgery show a success rate of approximately 80% in infantile glaucoma.6,11–13,16–25 Goniotomy appears to be as effective as external trabeculotomy in this condition. It appears that goniotomy is most successful in patients whose glaucoma is recognized early and treated between 1 month and 1 year of age. Early diagnosis and prompt treatment of this disease are important if good results are to be obtained, although good success rates are achieved in patients up to 2 years of age. The severity of the ﬁltration angle defect also determines the success with goniotomy. To evaluate whether a more extensive incision of the tissue adjacent to the anterior trabecular meshwork can result in more effective control of intraocular pressure, Catalano et al26 performed one versus two simultaneous goniotomies as the initial surgical procedure for primary infantile glaucoma. Successes of the two groups were not signiﬁcantly different at one month or at one year postoperatively, and the use of viscoelastic did not favorably or adversely affect intraocular pressure control.26 For the maintenance of a deep and stable anterior chamber during goniotomy, other surgeons also preferred viscoelastic substances.27–29

Trabecular meshwork

B

C

Figure 10.2 Goniotomy. The goniotomy knife is directed across the anterior chamber under direct visualization (A). Although the blade tip appears to enter Schlemm’s canal in panel B, more superficial incisions are also effective. The trabecular meshwork is circumferentially incised, in one direction (B) then the opposite direction (C). 66

Trabeculotomy ab externo Endoscopically controlled intraocular surgery has been evolving rapidly since the introduction of thinner endoprobes with increasing resolving power and higher image quality. The use of an endoscope for goniotomy surgery is a relatively new concept and only few animal studies and case reports have been published in the literature.30–34 Medow and Sauer30 were the ﬁrst to report that endoscopic goniotomy can be effective in treating primary congenital glaucoma. They performed endoscopic goniotomy in a 1500-g newborn with an intraocular pressure of 28 mmHg and signiﬁcant corneal clouding. The patient was followed for 2 years and intraocular pressure was controlled without medication, with pressure in the low teens. Recently, Bayaraktar and Koseoglu31 reported 12 eyes of 7 patients treated with endoscopic goniotomy with anterior chamber maintainer and concluded that the procedure was an effective treatment modality for congenital glaucoma even with totally opaque corneas. However, microendoscopy of the anterior segment of the eye creates a new surgical situation, so that great caution has to be exercised during the procedure. It demands technical adaptation, and the learning curve is steep.

Trabeculotomy ab externo Trabeculotomy ab externo, or external trabeculotomy, as practiced today is an alternative to goniotomy for the surgical treatment of congenital and childhood glaucomas and can be used when corneal opacity prevents an adequate gonioscopic view. Simultaneously and independently described by Burian35,37 and Smith36 in 1960, trabeculotomy ab externo has given results better than those with goniotomy. In March, 1960, without the aid of an operating microscope, the ﬁrst external trabeculotomy was performed by Burian on a young girl with Marfan syndrome and glaucoma.35 At about the same time in London, Redmond Smith developed an operation that he called ‘nylon ﬁlament trabeculotomy.’36 This involved cannulating Schlemm’s canal with a nylon suture at one site and threading the suture circumferentially and then withdrawing it at another site and pulling it tight like a bowstring. The surgical technique of trabeculotomy ab externo is basically a combination of the procedures originally developed by Burian and Smith, and later modiﬁed by Harms,38,39 Dannheim,40,41 and McPherson.23,42–43 Trabeculotomy ab externo has a number of major advantages over the alternative operation of goniotomy.44 First, a trabeculotomy can be performed with undiminished accuracy when the cornea is edematous or scarred, when there is poor visibility of the anterior chamber. Second, the procedure is anatomically precise in rupturing the inner wall of Schlemm’s canal and the trabecular meshwork, creating continuity between the anterior chamber and Schlemm’s canal. Third, trabeculotomy does not require the introduction of sharp instruments across the anterior chamber, which increases the risk of damage to other ocular tissues, especially for the inexperienced surgeon. Fourth, there is no need for the surgeon to adapt to the operating gonioprism, because the procedure is performed using the standard operating microscope and conventional anterior segment microsurgical techniques.

Advocates of trabeculotomy argue that the success of trabeculotomy depends only on the type of angle anomaly and is not dependent on the severity of the glaucoma, the size of the cornea, or the presence of corneal edema, which have been reported to influence the success of goniotomy.45,46 A lower incidence of postoperative cataract and few postoperative complications have been reported after trabeculotomy compared with goniotomy. Furthermore, goniotomy controls the intraocular pressure in about 64%45 to 77%11,46 of eyes having congenital glaucoma of all degrees of severity. If the eyes with corneal cloudiness are excluded, and in eyes where multiple goniotomies are performed, 85% can achieve control of intraocular pressure.46 Trabeculotomy, on the other hand, will control intraocular pressure in over 90% of eyes with glaucoma of all grades of severity, although some of these eyes required two or three procedures. Comparing these reported results of goniotomy and trabeculotomy suggests that trabeculotomy may achieve higher success rates compared with goniotomy when comparing eyes with all grades of severity. However, there are no prospective, controlled trials of trabeculotomy measured against goniotomy in the same study to conﬁrm this interpretation. Nonetheless, the popularity of trabeculotomy ab externo as an initial procedure in the surgical management of primary infantile glaucoma has been championed by a number of authorities.11,23,37–43,48–52 Trabeculotomy requires a few specialized instruments compared with trabeculectomy; in particular trabeculotomes are needed (Fig. 10.3). To perform trabeculotomy, a limbus-based conjunctival flap is prepared, with the conjunctival incision approximately 7 mm from the limbus (Fig. 10.4). Many surgeons prefer a fornix-based conjunctival flap, with the incision at the limbus, and this approach is necessary when exposure is not adequate to allow for a limbus-based conjunctival flap. Hemostasis is maintained throughout the dissection of the conjunctival flap, although cautery should be minimized to avoid excessive shrinkage of sclera. A partial thickness scleral flap is prepared, with its base at the limbus. The flap is usually an equilateral triangle, measuring approximately 3 to 4 mm on each side, although some surgeons prefer a rectangular-shaped flap. The authors prefer a triangular flap as it allows adequate exposure of Schlemm’s canal and involves less scleral dissection than a rectangular flap. The depth of the flap is approximately one-half scleral

Figure 10.3 Instruments for trabeculotomy. The trabeculotomes are designed for right- and left-sided passage into Schlemm’s canal. 67

Initial surgical treatment

A

B

C

Figure 10.4 Trabeculotomy. After preparation of a partial-thickness scleral flap, Schlemm’s canal is entered with a knife, the trabeculotome is passed into Schlemm’s canal (A), and the trabeculotome is rotated (B) in order to pass through trabecular meshwork into the anterior chamber (C).

thickness, bearing in mind that the sclera in buphthalmic eyes is usually much thinner than the adult eye. The surgical landmarks and anatomy of the limbal region should be carefully identiﬁed during the trabeculotomy. Closest to the limbus is a transparent band of deep corneal lamellae. Behind that is a narrow grayish-blue band, which represents the trabecular meshwork. Posterior to this area is white, opaque sclera. The junction of the posterior border of the trabecular band and the sclera is the external landmark of the scleral spur and the landmark for ﬁnding Schlemm’s canal. In most eyes this is situated between 2 and 2.5 mm behind the surgical limbus. A radial incision is then made across the scleral spur. The objective of this radial incision is to cut the external wall of Schlemm’s canal and to avoid entering the anterior chamber. It is important to bear in mind that Schlemm’s canal is separated from the anterior chamber only by the trabecular meshwork. This is the most delicate step in the operation and demands the most microsurgical skill. Under high magniﬁcation, the radial incision is gradually deepened with a sharp blade until it is carried through the external wall of Schlemm’s canal, at which point there is ooze of aqueous, occasionally mixed with blood. The dissection is carefully continued through the external wall until the inner wall of the canal becomes visible. The inner wall is characteristically slightly pigmented and is composed of crisscrossing ﬁbers. Vannas scissors are used to enlarge the lumen of the canal. Some surgeons conﬁrm passage into the canal by passing a 6–0 nylon suture into the canal, as described by Smith.36 The internal (lower or distal) arm of the trabeculotome is introduced into the canal using the external (upper or proximal) parallel arm as a guide. Once 90% of the trabeculotome is within the canal, it is rotated into the anterior chamber and rotation is continued until 75% of the probe arm length has entered the chamber, then the rotation is reversed and the instrument is withdrawn. About 2 to 21/2 clock hours of the internal wall of Schlemm’s canal and trabecular meshwork are disrupted by the rotation of the trabeculotome into the anterior chamber. The trabeculotome

68

is then passed into the Schlemm’s canal on the other side of the radial incision and rotated into the anterior chamber. In total, about 100 to 120 degrees of trabecular meshwork is ruptured by this technique. It is important that no force be used when introducing the probe into the canal, as this will create a false passage. If the probe does not slip easily down the canal, it should be withdrawn and dissection of the outer wall continued until the surgeon is satisﬁed that all ﬁbers of the outer wall are removed. The probe is then re-introduced into the canal. As the probe passes into the anterior chamber, disrupting the inner wall of the canal, there should be some slight resistance and there may be a little intracameral bleeding from the inner wall.23,42– 43 This is a transient sign, usually resolving within a few days after the surgery. As the probe is swung from the canal into the anterior chamber, movement of the iris may indicate that the probe is too posterior. The probe should be repositioned to avoid iridodialysis. The cornea should also be carefully monitored to ensure that the probe is not passing anteriorly into the cornea, requiring repositioning of the probe. This is easy to detect because small air bubbles appear in the cornea as the probe ruptures corneal lamellae. In highly buphthalmic eyes, Schlemm’s canal may not be located with certainty. In such cases it is possible to convert the procedure to a trabeculectomy by removing a block of deep limbal tissue beneath the scleral flap. The surgical technique of trabeculotomy ab externo is possible even in the presence of severe corneal edema. There are several successful reports of primary trabeculotomy for developmental glaucoma.23,38–44,53–54 While goniotomy is reported to be safe and successful when performed by experienced surgeons, trabeculotomy ab externo offers the advantage of being more predictable and technically easier. The advantages of trabeculotomy ab externo over the alternative procedure of goniotomy have been reported by Luntz.44 McPherson and Berry23 reported a higher success rate with trabeculotomy as the initial procedure compared to goniotomy, but Anderson22,55 and Shaffer50 reported that the

Primary trabeculectomy

Primary trabeculectomy Trabeculectomy is a procedure with which most ophthalmologists are familiar and it is technically easier than goniotomy or trabeculotomy. However primary trabeculectomy is not a ﬁrst-line procedure in congenital glaucoma in view of a higher incidence of complications and lower success rate in normalizing intraocular pressure.61–63 In contrast several published reports have documented successful results following primary trabeculectomy for congenital glaucoma that are comparable to or are higher than some of the reported series on goniotomy or trabeculotomy.64–69

A

IOP (mmHg)

40

Primary glaucoma Secondary glaucoma

30 20 10 0

0

5

10 Time (years)

15

20

B 100 Survival probability

two procedures were equally effective. Shields and Krieglstein56 recommended that the surgeon focus on only one of the two procedures to gain experience in managing this rare disease. Filous and Brunova57 reported the results of modiﬁed trabeculotomy in the treatment of primary congenital glaucoma employing trabeculotomy probes more closely corresponding to the variable course of Schlemm’s canal. They reported a success rate of 87% over a mean follow-up of 38.4±22.5 months and concluded that probing with the innovative instrument was easier and safer compared to standard trabeculotomy probes. A newer trabeculotomy technique with a prolene suture was recently developed by Beck and Lynch.58 They reﬁned a technique for performing 360 degree trabeculotomy in a single procedure using a 6–0 polypropylene (Prolene) suture fragment and have used it in 15 patients (26 eyes) with primary congenital glaucoma. The reﬁned technique can be performed via a single nasal surgical site. This procedure avoids many of the difﬁculties encountered with metal trabeculotomes and preserves conjunctiva should further glaucoma surgery be necessary. Recently, Mendicino et al59 compared the long-term surgical results of 360 degree trabeculotomy and goniotomy and reported signiﬁcantly better intraocular pressure control with the former technique as they believed that it is more standardized than the latter technique. Additional controlled and randomized studies comparing the two techniques will reveal which one is more efﬁcient and safer in the management of congenital glaucoma. The long-term outcome of trabeculectomy for the treatment of developmental glaucoma has been described. McPherson and Berry found that 22 (96%) of 23 eyes were controlled at intraocular pressure under 21 mmHg at the ﬁnal visit (mean follow-up, 5.6 years).23 Ikeda and co-workers reviewed 112 eyes with primary developmental glaucoma, with an average intraocular pressure of 15.6 ± 5.0 mmHg at an average follow-up of 9.5 ± 7.1 years.60 At the ﬁnal visit, trabeculectomies in 100 (89.3%) of the 112 eyes were deﬁned as successes (intraocular pressure less than 21 mmHg with no enlargement of the optic disc cup or corneal diameter). A life-table analysis showed success probability of 80.8% at 20 years after the ﬁrst trabeculotomy in eyes with primary developmental glaucoma.60 Eyes with infantile glaucoma had better success rates and mean intraocular pressures compared with secondary developmental glaucoma (Fig. 10.5).

80 60 40 20 0

Primary glaucoma Secondary glaucoma 0

5

10

15 Time (years)

20

25

30

Figure 10.5 Long-term outcome after trabeculotomy. The mean intraocular pressure remained in the normal range during the follow-up period after the initial trabeculotomy (A). The success rate was higher for eyes with primary glaucoma compared to those with secondary glaucoma (B). At the latest follow-up visit, the percent success was 89%. Modified with permission from Ikeda H, Ishigooka H, Muto T, et al. Long-term outcome of trabeculotomy for the treatment of developmental glaucoma. Arch Ophthalmol 2004; 122:1122–1128 Copyright © (2004) American Medical Association. All rights reserved.

Ab externo combined trabeculotomy and trabeculectomy Combined trabeculotomy and trabeculectomy may be performed as a primary or secondary procedure. The procedure is used as a primary procedure in patients that have a poor prognosis for success of initial goniotomy or trabeculotomy, such as patients in the Middle East or India, or patients over 2 years of age. The operative procedure and the postoperative appearance are shown in Fig. 10.6. After performing the trabeculotomy as described above, the trabeculectomy may be performed by making an incision at the surgical limbus with a sharp blade and using the Descemet’s punch to create a sclerostomy. Alternatively, a block of sclera may be removed using a sharp blade and Vannas scissors. After performing a surgical iridectomy, the partial thickness flap is closed with interrupted sutures, usually one at the apex and one on each lateral side of the triangular flap. These may be 10–0 nylon sutures, or, alternatively, absorbable sutures such as 9–0 polyglactin or 10–0 BioSorb sutures may be used to encourage aqueous flow during the postoperative period. Conjunctiva and Tenon’s

69

Initial surgical treatment

A

B

C

D

E

F

G

H

I

J

Figure 10.6 Combined trabeculotomy and trabeculectomy. The conjunctival incision may be either a fornix-based or limbal-based flap. A limbal-based flap is shown in these photographs. A partialthickness scleral flap is prepared (A). Some surgeons use intraoperative mitomycin-C after this step. Schlemm’s canal is identified (B), and the trabeculotome is passed into Schlemm’s canal (C). The trabeculotome is rotated into the anterior chamber (D), which is often accompanied by bleeding from Schlemm’s canal. The other trabeculotome is passed in the opposite direction and rotated into the anterior chamber (E). After completion of the trabeculectomy, a sclerostomy is prepared (F). A Descemet’s punch may be used to prepare the sclerostomy. A peripheral iridectomy is performed, and the scleral flap is closed with interrupted sutures (G). The conjunctival incision is closed with a running suture (H). In this eye, the corneal edema cleared, and the intraocular pressure remained stable during the postoperative period. The appearance of the eye is shown at 3 years after the procedure (I, J).

capsule are then closed with a running suture of an absorbable material (e.g. 8–0 or 9–0 polyglactin). Most surgeons perform a paracentesis opening with a beveled corneal incision at the beginning of the surgery. Through the paracentesis, the anterior chamber can be reformed with balanced salt solution and patency of the trabeculectomy can be tested at the conclusion of the surgery. Also, identiﬁcation of Schlemm’s canal may be facilitated when the intraocular pressure is lowered after the paracentesis. Subconjunctival injection of an antibiotic–steroid preparation is performed, topical antibiotic–steroid medica70

tions are placed into the conjunctival fornix, and a patch and shield are applied to the eye. The dressing is removed on the ﬁrst postoperative day. An antibiotic–steroid combination is prescribed four times a day. A cycloplegic (e.g., cyclopentolate 1% BID) is used only if the eye has a shallow anterior chamber and the child is seen frequently in the ofﬁce for monitoring. Examination of the patient under anesthesia is performed approximately 3 to 4 weeks after surgery. If all is stable, the patient is scheduled for another evaluation under anesthesia in approximately 3 months. The evaluations may be repeated at quarterly

Long-term follow-up and prognosis 1.0 Survival probability

intervals for the ﬁrst year after surgery. After the ﬁrst year, the examinations are biannual until the child is old enough to cooperate fully with an ofﬁce examination. Ofﬁce visits may reduce the need for examinations under anesthesia. These patients should be followed up for an indeﬁnite time to determine whether or not adequate control of intraocular pressure has been achieved. The success rate is high for children with infantile glaucoma and surgery within the ﬁrst year of life, whereas patients with Sturge–Weber syndrome have increased failure with longer follow-up. Whether combined trabeculotomy–trabeculectomy is superior to trabeculotomy alone is debatable. Biedner and Rothkoff70 found no difference between trabeculotomy and combined trabeculotomy–trabeculectomy in a small series of 7 patients with congenital glaucoma. Dietlein et al71 investigated the outcome of trabeculotomy, trabeculectomy and a combined procedure as initial surgical treatment approaches in primary congenital glaucoma. Although the combined procedure seemed to have a favorable outcome, after 2 years the advantages of this procedure over trabeculotomy or trabeculectomy was not statistically signiﬁcant according to the life table analysis. Elder72 compared primary trabeculectomy with combined trabeculotomy–trabeculectomy and found the combined procedure to be superior. The superior results of the combined procedure may be because of the dual outflow pathway as explained by Elder. Mullaney et al73 and Al-Hazmi et al74 used mitomycin-C in primary combined trabeculotomy–trabeculectomy and reported a higher success rate. The results reported by Mandal et al75–81 from India are comparable to that reported by Mullaney et al and Al-Hazmi et al from Saudi Arabia but Mandal et al did not use mitomycin-C in primary surgery. The long-term results of trabeculectomy–trabeculotomy have been described by Mandal et al,81 who reported longterm outcome of 299 eyes of 157 consecutive patients who underwent primary combined trabeculotomy–trabeculectomy for developmental glaucoma by a single surgeon over a 12 year period. Kaplan–Meier survival analysis demonstrated the success probabilities of 94.4%, 92.0%, 86.7%, 79.4%, 72.9% and 63% at the 1st, 2nd, 3rd, 4th, 5th, and 6th year, respectively (Fig. 10.7). The success rate of 63.1% was maintained until 8 years of follow-up. Data on visual acuity was available in 49 patients. At the ﬁnal follow-up visit, 20 patients (40.8%) had normal visual acuity (best-corrected visual acuity of better than or equal to 20/60 in the better eye). The compelling argument in favor of primary combined trabeculotomy–trabeculectomy in some ethnic populations is the higher incidence of successful intraocular pressure control with a single operative procedure, as has been reported from India and Saudi Arabia. O’Connor82 commented that combined trabeculotomy–trabeculectomy is potentially a very successful surgical procedure in the management of congenital glaucoma and may represent the next step in the search for the best surgical treatment of congenital glaucoma. Further prospective randomized studies are required to explore the surgical results of trabeculotomy, primary combined trabeculotomy and trabeculectomy, and 360° trabeculotomy. However such a study is difﬁcult to conduct because most

0.8 0.6 0.4 0.2 0.0

0

1

2

3 4 5 6 Follow-up duration (years)

7

8

9

Figure 10.7 Long-term success after combined trabeculotomy and trabeculectomy. Children with developmental glaucoma were operated within 6 months of birth, with 142 eyes included in the analysis. Surgery was considered a complete success when the intraocular pressure was less than 21 mmHg in patients examined under general anesthesia or less than 21 mmHg in patients who were old enough to be examined with the slit lamp, and when there was no progression of disc cupping or corneal diameter. The Kaplan–Meier curve shows the complete success probabilities. Modified with permission from Mandal AK, Bhatia PG, Bhaskar A, Nutheti R. Long-term surgical and visual outcomes in Indian children with developmental glaucoma operated on within 6 months of birth. Ophthalmology 2004; 111:283–290.

glaucoma specialists are better trained in and more comfortable with one angle procedure than the other.

Long-term follow-up and prognosis Between 3 and 6 weeks after surgery, the postoperative control of the glaucoma must be judged. The degree of relief from photophobia, tearing, and blepharospasm usually reflect the effectiveness of surgery and may reasonably predict whether or not additional surgery will be required. Children with developmental glaucoma must be re-examined periodically and for an indeﬁnite time to determine whether or not adequate control of intraocular pressure has been achieved. Most of the examination can be done in an ofﬁce setting. Examination under anesthesia often allows more careful gonioscopy, in addition to other measurements. Each followup evaluation should include vision testing, external examination, refraction, ophthalmoscopy, corneal assessment, and tonometry. Gonioscopy, ultrasonographic biometry, and disc photography are performed as needed. Vision testing techniques vary greatly with the age of the patient. In infants, good ﬁxation and following as well as the absence of nystagmus are important indicators of good visual function. In children over 3 years of age, visual acuity and, eventually, visual ﬁelds can also be determined. The external examination is important in order to detect evidence of associated abnormalities, inflammation, or lacrimal duct obstruction. Subjective refraction is generally not possible, but retinoscopy of the eye can be compared to previous measurements of myopia and astigmatism. The optic disc can be examined by ophthalmoscopy to determine if the optic cup has remained the same, enlarged, or regressed.53 The cornea is assessed, the degree of corneal haze or edema is 71

Initial surgical treatment Figure 10.8 Clinical appearance of child with unilateral corneal edema due to congenital glaucoma (A). The postoperative appearance of the child, showing resolution of corneal edema (B).

A

B

noted (Fig. 10.8), and calipers are used to measure the corneal diameter. A problem with calipers in measuring corneal diameter is that it is difﬁcult to distinguish the actual corneal diameter from a cord length. Accurate measurements of the corneal diameter are facilitated by the use of a plastic gauge with calibrated holes.83 Tonometry is best performed on the peaceful, awake infant. If an examination under anesthesia is required, tonometry is performed at an appropriate stage of anesthesia,84 but the signiﬁcance of the intraocular pressure reading must be balanced carefully against the other clinical signs, if it is not in keeping with them. Many anesthetics alter intraocular pressure of patients with developmental glaucomas. Postoperatively, gonioscopy provides important anatomic information about the status of the anterior chamber angle treated with goniotomy or trabeculotomy ab externo. Ultrasonographic biometry may be performed, utilizing the A-scan ultrasound to measure axial length compared to presurgical readings. Sampaolesi85 and many other authors86–88 have stressed the clinical importance of echography in the diagnosis and follow up of the developmental glaucomas. Disc photography may provide a record for future comparisons. A decrease in cupping can occur within hours or days after intraocular pressure control in the very young. This is especially marked in infants below 1 year of age. The prognosis of this disease is related to the time of its initial presentation, initial surgical intervention, degree of optic nerve damage, nature and quality of corneal enlargement, astigmatism, progressive refractive error, and anisometropic amblyopia.89 The inability to easily quantitate visual acuity and extent of visual loss in neonates and children makes these variables less helpful in following patients than measurements of corneal diameter and intraocular pressure. However, these data should not be relied upon exclusively to determine the success of treatment in developmental glaucoma. Because of difﬁculties measuring intraocular pressure and visual ﬁelds in children, ophthalmoscopy often provides the most reliable information of elevated intraocular pressure as seen by cupping of the optic nerve. Continued enlargement 72

of the globe, as seen by retinoscopy and/or ultrasonography, signiﬁes inadequately controlled pressure; while stability (and sometimes slight reduction90) of ocular size suggests adequate control of intraocular pressure during the long-term follow-up. In properly selected patients, namely those with isolated trabeculodysgenesis, surgical treatment (trabeculotomy ab externo or goniotomy) is often successful. It should be remembered, however, that increased intraocular pressure can occur at any time in the life of the patient and lifelong follow-up is necessary. The most important variables in the follow-up examinations are cupping of the optic disc visualized by ophthalmoscopy, axial length values measured by ultrasonographic biometry, intraocular pressure measured by applanation tonometry, and visual ﬁeld evaluation (if possible). Long-term vision outcomes have been described in patients with developmental glaucomas.10,20,21,24,54,57,59,60,75,79,81,91–96 The vision outcome in studies of children with developmental glaucomas are summarized in Table 10.1. The prognosis for vision is variable, with some children achieving poor outcomes while many experience good vision outcome.

Conclusion The responsibility of the surgeon does not end with surgery, and it is important not to be lulled into a false sense of security by surgical control of intraocular pressure. Visual rehabilitation is as important in the management of the disease as is intraocular pressure control. Visual rehabilitation involves correction of refractive errors, correction of opacities in the media, including corneal scarring and cataract, and orthoptic treatment to stimulate the development of binocular stereoscopic vision. Anisometropia and amblyopia must be aggressively managed to give these children the best chance for good vision in both eyes. An attempt should be made to familiarize the parents with the protracted nature of the illness, the prognosis, the frequent necessity for repeat surgery, and the life-long necessity for

References

Table 10.1 Studies of visual outcome for developmental glaucoma Year

Type of glaucoma

No. of subjects or eyes

Best-corrected visual acuity

Scheie

1959

Infantile glaucoma

53 eyes

≥20/50 (60% eyes)

Richardson et al20

1967

Infantile glaucoma

NA

≥20/50 (39% eyes) ≤20/200 (40% eyes)

Hass10

1968

Infantile glaucoma

NA

>20/50 (39%)

Biglan and Hiles92

1979

Infantile glaucoma

25 eyes

≥20/50 (64% eyes)

94

Robin et al

1979

Infantile glaucoma

102 eyes

>20/50 (41%; 30 eyes) <20/200 (41%; 30 eyes)

Broughton and Parks21

1981

Congenital glaucoma

29 eyes

≥20/40 (15 eyes) ≥20/60 (20 eyes)

Morgan et al93

1981

Congenital glaucoma

12 eyes

≥20/50 (58%; 7 eyes) 20/100 (9 eyes)

Shaffer24

1982

Developmental glaucoma

52 eyes

20/20–20/40 (28 eyes) 20/50–20/200 (11 eyes) <20/200 (13 eyes)

Akimoto et al54

1994

Developmental glaucoma

111 eyes

>20/40 (68 eyes) 20/200–20/40 (23 eyes) <20/200 (20 eyes)

Mandal et al75

1998

Juvenile-onset developmental glaucoma

38 eyes

<20/200 (50%;19 eyes) 20/200 (26.3%; 10 eyes) 20/100–20/40 (7.8%; 3 eyes) >20/40 (15.7%; 6 eyes)

Mendicino et al59

2000

Congenital glaucoma

24 eyes (trab.) 40 eyes (gonio.)

≥20/50 (79.2%; 19 eyes) ≥20/50 (52.5%; 21 eyes)

Meyer et al95

2000

Congenital glaucoma

35 eyes

Within normal nomogram range in 12 eyes

Mandal et al79

2002

Developmental glaucoma

28 eyes

<20/200 (28.6%; 8 eyes) 20/200–20/50 (28.6%; 8 eyes) >20/50 (42.9%; 12 eyes)

Filous and Brunova57

2002

Congenital glaucoma

78 eyes

20/20–20/40 (64.1%) <20/40 (35.9%)

MacKinnon et al96

2004

Infantile glaucoma

83 eyes

20/40 or better (61.8%)

Mandal et al81

2004

Developmental glaucoma

49 patients

20/60 or better (40.8%)

2004

Developmental glaucoma

131 eyes

≥20/40 (59.5%, 78 eyes) 20/40–20/200 (16.0%, 21 eyes) <20/200 (24.4%, 32 eyes)

Author(s) 91

Ikeda et al

60

NA, not available.

continued examinations. The parents may be quite young, and may be emotionally and economically ill-equipped to cope with the problems that have suddenly and dramatically occurred. Their guilt problems must be assuaged, particularly if a family history of congenital glaucoma exists. The parents should also be familiarized with the various agencies that will afford ﬁnancial assistance when necessary. Time and effort well-spent will reward the ophthalmologist many times over at a later date. Fortunately, with early diagnosis and microsurgical techniques, the large majority of these eyes can be controlled if not completely cured. However, in a few patients who continue to show poor response to surgery, such operations may delay loss of vision and allow the child to develop visual images that will be valuable to him or her in later life. Eventually, the social aspects of the glaucomatous child will require repeated counseling. Poor vision will need explanation to the parents and schools, the child may require the help of visual aids,

and cosmetic blemishes will need correction where possible. Continued clinical monitoring combined with adequate social support should allow the best possible outcome for the child.

References 1. Barkan O. A new operation for chronic glaucoma. Am J Ophthalmol 1936; 19:951. 2. Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217–221. 3. Barkan O. Operation for congenital glaucoma. Am J Ophthalmol 1942; 25:552–568. 4. Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 1948; 32:701–728. 5. Barkan O. Techniques of goniotomy for congenital glaucoma. Arch Ophthamol 1949; 41:65–68. 6. Barkan O. Surgery of congenital glaucoma. Review of 196 eyes operated by goniotomy. Am J Ophthalmol 1953; 36:1523–1534. 7. Barkan O. Pathogenesis of congenital glaucoma. Gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955; 40:1–11.

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Initial surgical treatment 8. Barkan O. Goniotomy. Trans Am Acad Ophthalmol 1955; 589:322–332. 9. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Trans Am Ophthalmol Soc 1962; 60:140–162. 10. Hass J. Principles and problems of therapy in congenital glaucoma. Invest Ophthalmol 1968; 7:140–146. 11. Haas JS. Congenital glaucoma. End results of treatment. Trans Am Acad Ophthalmol Otolaryngol 1955; 59:333–340. 12. Scheie HG. Management of infantile glaucoma. Arch Ophthalmol 1959; 62:35–54. 13. Shaffer RN. New concepts in infantile glaucoma. Can J Ophthalmol 1967; 2:243–247. 14. Shaffer RN, Hetherington J. Glaucomatous disc in infants, a suggested hypothesis for disc cupping. Trans Am Acad Ophthalmol Otolaryngol 1969; 73:929–935. 15. Shaffer RN, Weiss DI. The congenital and pediatric glaucomas. CV Mosby: St Louis, MO; 1970. 16. Bietti GB. Contribution a la connaissance des resultats de la goniotomie dans le glaucoma congenitable. Ann Ocul (Paris) 1966; 199:481–485. 17. Morgan KS, Black B, Ellis FD, Helveston EM. Treatment of congenital glaucoma. Am J Ophthalmol 1981; 92:799–803. 18. Moller PM. Goniotomy and congenital glaucoma. Acta Ophthalmol 1977; 55:436–442. 19. Morin JD. Congenital glaucoma. Trans Am Ophthalmol Soc 1980; 78:123. 20. Richardson KT, Ferguson WJ Jr, Shaffer RN. Long-term functional results in infantile glaucoma. Trans Am Acad Ophthalmol Otolaryngol 1967; 71:833–836. 21. Broughton WL, Parks MM. Analysis of treatment of congenital glaucoma by goniotomy. Am J Ophthalmol 1981; 91:566–572. 22. Anderson DR. In discussion of Quigley HA: Childhood glaucoma. Ophthalmology 1982; 90:225–226. 23. McPherson SD Jr, Berry DP. Goniotomy vs external trabeculotomy for developmental glaucoma. Am J Ophthalmol 1983; 95:427–431. 24. Shaffer RN. Prognosis of goniotomy in primary infantile glaucoma (trabeculodysgenesis). Trans Am Ophthalmol Soc 1982; 80:321–325. 25. Shaffer RN, Hoskins HD. Montgomery lecture. Goniotomy in the treatment of isolated trabeculodysgenesis (primary congenital [infantile] developmental glaucoma). Trans Ophthalmol Soc UK 1983; 103:581–585. 26. Catalano RA, King RA, Calhoun JH, Sargent RA. One versus two simultaneous goniotomies as the initial surgical procedure for primary infantile glaucoma. J Pediatr Ophthalmol Strabismus 1989; 26:9–13. 27. Arnoult J, Vila Coro A, Mazow M. Goniotomy with sodium hualuronate. J Pediatr Ophthalmol Strabismus 1988; 25:18–22. 28. Winter R. Technical modiﬁcation in goniotomy using high viscous hyaluronic acid. Dev Ophthalmol 1985; 11:136–138. 29. Hodapp E, Heuer D. A simple technique for goniotomy. Am J Ophthalmol 1986; 102:537. 30. Medow NB, Sauer HL. Endoscopic goniotomy for congenital glaucoma. J Pediatr Ophthalmol Strabismus 1997; 34:258–259. 31. Bayraktar S, Koseoglu T. Endoscopic goniotomy with anterior chamber maintainer: Surgical technique and one year results. Ophthalmic Surg Lasers 2001; 32:496–502. 32. Joos KM, Alward WL, Folberg R. Experimental endoscopic goniotomy. A potential treatment for primary infantile glaucoma. Ophthalmology 1993; 100:1066–1070. 33. Joos KM, Shen JH. An ocular endoscope enables a goniotomy despite a cloudy cornea. Arch Ophthalmol 2001;119:134–135. 34. Sun W, Shen JH, Shetlar DJ, Joos M. Endoscopic goniotomy with the free electron laser in congenital glaucoma rabbits. J Glaucoma 2000; 116:199–202. 35. Burian HM. A case of Marfan’s syndrome with bilateral glaucoma with a description of a new type of operation for developmental glaucoma. Am J Ophthalmol 1960; 50:1187–1192. 36. Smith R. A new technique for opening the canal of Schlemm. Br J Ophthalmol 1960; 44:370–373. 37. Burian HM, Allen L. Trabeculotomy ab externo; a new glaucoma operation: Technique and results of experimental surgery. Am J Ophthalmol 1962; 53:19–26. 38. Harms H, Dannheim R. Epicritical consideration of 300 cases of trabeculotomy ab externo. Trans Ophthalmol Soc UK 1969; 89:491–499. 39. Harms H, Dannheim R. Trabeculotomy results and problems. In: Machensen G, ed. Microsurgery Study Group, Burgenstock, 1968. Adv Ophthalmol 1970; 22:121–130. 40. Dannheim R. Trabeculotomy. Techniques and results. Arch Chili Oftal 1971; 28:149–157. 41. Dannheim R. Trabeculotomy. Trans Am Acad Ophthalmol Otolaryngol 1972; 76:375–383. 42. McPherson SD Jr. Results of external trabeculotomy. Am J Ophthalmlogy 1973; 76:918–920.

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43. McPherson SD, McFarland D. External trabeculotomy for developmental glaucoma. Ophthalmology 1980; 87:302–305. 44. Luntz MH. The advantages of trabeculotomy over goniotomy. J Pediatr Ophthalmol Strabismus 1984; 21(4):150–153. 45. Hetherington J Jr. Congenital glaucoma. In: Duane TD, ed. Clinical ophthalmology. Harper & Row: New York; 1982:4. 46. Hass H. Glaucoma in infants and children. In: Kwitko ML, ed. Glaucoma in infants and children. Appleton-Century-Crofts: New York; 1973:483–603. 47. Gregerson E, Kessing SVV. Congenital glaucoma before and after the introduction of microsurgery. Results of ‘Macro-surgery’ 1943–1963 and of microsurgery (Trabeculotomy/ectomy) 1970–1974. Acta Ophthalmol 1977; 55:422–430. 48. Luntz MH. Primary buphthalmos (infantile glaucoma) treated by trabeculotomy ab externo. S Afr Arch Ophthalmol 1974; 2:319–334. 49. Luntz MH, Livingston DG. Trabeculotomy ab externo and trabeculectomy in congenital and adult-onset glaucoma. Am J Ophthalmol 1977; 83:174–179. 50. Hoskins HD, Shaffer RN, Hetherington J. Goniotomy vs trabeculotomy. J Pediatr Ophthalmol Strabismus 1984; 21(4):153–158. 51. Kiffney GT, Meyers GW, McPherson SD Jr. The surgical management of congenital glaucoma. South Med J 1960; 53:989–995. 52. Luntz MH. Congenital, infantile, and juvenile glaucoma. Ophthalmology 1979; 86:793–802. 53. Quigley HA. Childhood glaucoma: Results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–225. 54. Akimoto M, Tanihara H, Negi A, Nagata M. Surgical results of trabeculotomy ab externo for developmental glaucoma. Arch Ophthalmol 1994; 112:1540–1544. 55. Anderson DR. Trabeculotomy compared to goniotomy of glaucoma in children. Ophthalmology 1983; 90:805–806. 56. Shields MB, Krieglstein GK. Glaukom: Grundlagen. Differential diagnose, Therapie. Springer: Berlin; 1993:50–78, 211–225, 527–532. 57. Filous A, Brunova B. Results of the modiﬁed trabeculotomy in the treatment of primary congenital glaucoma. J AAPOS 2002; 6:182–186. 58. Beck AD, Lynch MG. 360° trabeculotomy for primary congenital glaucoma. Arch Ophthalmol 1995; 113:1200–1202. 59. Mendicino ME, Lynch MG, Drack A, et al. Long-term surgical and visual outcomes in primary congenital glaucoma: 360° trabeculotomy versus goniotomy. J AAPOS 2000; 4:205–210. 60. Ikeda H, Ishigooka H, Muto T, Tanihara H, Nagata M. Long-term outcome of trabeculotomy for the treatment of developmental glaucoma. Arch Ophthalmol 2004; 122:1122–1128. 61. Beauchamp GR, Parks MM. Filtering surgery in children: barriers to success. Ophthalmology 1979; 86:170–180. 62. Cadera W, Pachtman MA, Cantor LB, et al. Filtering surgery in childhood glaucoma. Ophthalmic Surg 1984; 15:319–322. 63. Levene RZ. Glaucoma ﬁltering surgery: factors that determine pressure control. Ophthalmic Surg 1984; 15:475–483. 64. Joseph A. Trabeculectomy in congenital glaucoma. Indian J Ophthalmol 1981; 29:81–82. 65. Debnath SC, Teichmann KD, Salamah K. Trabeculectomy versus trabeculotomy in congenital glaucoma. Br J Ophthalmol 1989; 73:608–611. 66. Rao KV, Sai CM, Babu BVN. Trabeculectomy in congenital glaucoma. Indian J Ophthalmol 1984; 32:439–440. 67. Burke JP, Bowell R. Primary trabeculectomy in congenital glaucoma. Br J Ophthalmol 1989; 73:186–190. 68. Miller MH, Rice NSC. Trabeculectomy combined with beta irradiation for congenital glaucoma. Br J Ophthalmol 1991; 75:584–590. 69. Fulcher T, Chan J, Lanigan B, et al. Long-term follow up of primary trabeculectomy for infantile glaucoma. Br J Ophthalmol 1996; 80:499–502. 70. Biedner BZ, Rothkoff L. Combined trabeculotomy-trabeculectomy compared with primary trabeculotomy for congenital glaucoma. J Pediatr Ophthalmol Strabismus 1998; 35:49–50. 71. Dietlein TS, Jacob PC, Krieglstein GK. Prognosis of primary ab externo surgery for primary congenital glaucoma. Br J Ophthalmol 1999; 83:317–322. 72. Elder MJ. Combined trabeculotomy-trabeculectomy compared with primary trabeculectomy for congenital glaucoma. Br J Ophthalmol 1994; 78:745–748. 73. Mullaney PB, Selleck, Al-Award A, et al. Combined trabeculotomy and trabeculectomy as initial procedure in uncomplicated congenital glaucoma. Arch Ophthalmol 1999; 117:457–460. 74. Al-Hazmi A, Zwaan J, Awad A, et al. Effectiveness and complications of mitomycin-C use during pediatric glaucoma surgery. Ophthalmology 1998; 105:1915–1920. 75. Mandal AK, Naduvilath TJ, Jayagandhan A. Surgical results of combined trabeculotomy-trabeculectomy for developmental glaucoma. Ophthalmology 1998; 105:974–982

References 76. Mandal AK. Current concepts in the diagnosis and management of developmental glaucomas. Indian J Ophthalmol 1993;41:51–70. 77. Mandal AK. Microsurgical technique combines trabeculotomy and trabeculectomy to treat developmental glaucoma. Ocular Surgery News, International edition 1994; 5(8):38–43. 78. Mandal AK. Primary combined trabeculotomy-trabeculectomy for early onset glaucoma in Sturge-Weber syndrome. Ophthalmology 1999; 106:1621–1627. 79. Mandal AK, Bhatia PG, Gothwal VK, et al. Safety and efﬁcacy of simultaneous bilateral primary combined trabeculotomy-trabeculectomy for developmental glaucoma in India. Indian J Ophthalmol 2002; 50:13–19. 80. Mandal AK, Gothwal VK, Bagga H, Nutheti R, Mansoori T. Outcome of surgery on infants younger than 1 month with congenital glaucoma. Ophthalmology 2003; 110:1909–1915. 81. Mandal AK, Bhatia PG, Bhaskar A, Nutheti R. Long-term surgical and visual outcomes in Indian children with developmental glaucoma operated on within 6 months of birth. Ophthalmology 2004; 111:283–290. 82. O’Connor G. Combined trabeculotomy-trabeculectomy for congenital glaucoma (Editorial). Br J Ophthalmol 1994; 78:735. 83. Kiskis AA, Markowitz SN, Mortin JD. Corneal diameter and axial length in congenital glaucoma. Can J Ophthalmology 1985; 20:93–97. 84. Dominguez J, Banos MS, Alvarez MT, et al. Intraocular pressure measurement in infants under general anesthesia. Am J Ophthalmol 1974; 78:110–116. 85. Sampaolesi R, Caruso R. Ocular echometry in the diagnosis of congenital glaucoma. Arch Ophthalmol 1982; 100:s574–577.

86. Reibaldi A. Biometric ultrasound in the diagnosis and follow-up of congenital glaucoma. Ann Ophthalmol 1982; 14:707–708. 87. Tarkkanen A, Vusitalo R, Mianowicz J. Ultrasonographic biometry in congenital glaucoma. Acta Ophthalmol 1983; 61:618–623. 88. Law SK, Bui D, Caprioli J. Serial axial length measurements in congenital glaucoma. Am J Ophthalmol 2001; 132:926–928. 89. deLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19. 90. Morin JD, Merin S, Sheppard RW. Primary congenital glaucoma: A survey. Can J Ophthalmol 1974; 9:17–28. 91. Scheie, Harold G. The management of infantile glaucoma. Arch Ophthalmol 1959; 62:35–54. 92. Biglan AW, Hiles DA. The visual results following infantile glaucoma surgery. J Pediatr Ophthalmol Strabismus 1979; 16:377–381. 93. Morgan KS, Black B, Ellis FD, Helveston EM. Treatment of congenital glaucoma. Am J Ophthalmol 1981; 92:799–803. 94. Robin AL, Quigley HA, Pollack IP, Maumenee AE, Maumenee IH. An analysis of visual acuity, visual ﬁelds, and disc cupping in childhood glaucoma. Am J Ophthalmol 1979; 88:847–858. 95. Meyer G, Schenn O, Pfeiffer N, Grehn F. Trabeculotomy in congenital glaucoma. Graefes Arch Clin Exp Ophthalmol 2000; 238:207–213. 96. MacKinnon JR, Giubilato A, Elder JE, Craig JE, Macey DA. Primary infantile glaucoma in an Australian population. Clin Exp Ophthalmol 2004; 32:14–18.

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Chapter 11 Simultaneous surgery for bilateral congenital glaucoma Introduction Risks of surgery Anesthetic risks Simultaneous bilateral surgery Conclusion

Introduction The management of congenital glaucoma involves careful assessment, planning, and long-term care. In about two-thirds of the patients, congenital glaucoma is bilateral.1,2 The proposal of bilateral surgery for congenital glaucoma in one surgical session has been controversial. Many pediatric ophthalmologists strongly oppose this view because of the risks of bilateral sight-threatening complications such as endophthalmitis. The risk of general anesthesia in infants, however, is still a major concern for congenital glaucoma surgery. If bilateral anti-glaucoma surgery is not performed in the same operative session, the afflicted children must undergo two separate general anesthetics for their bilateral congenital glaucoma. The aim of this chapter is to compare the safety of simultaneous bilateral surgery in children with congenital glaucoma versus the risk of more than one general anesthesia within a short time period. The clinical appearance of a patient treated with simultaneous bilateral surgery for congenital glaucoma is shown in Fig. 11.1.

Risks of surgery Because of the anesthetic risks in infants, bilateral simultaneous goniotomies for congenital glaucoma were performed by Litinsky et al in 1977.3 Their particular interest was to

evaluate the risks of operating on two eyes during the same anesthesia. All the goniotomies were performed by three surgeons (Shaffer, Hetherington, and Hoskins). A separate sterile setup was used for each eye. There were no infections in this series and no complications could be attributed to the performance of surgery on both eyes during a single anesthesia. The most serious complication was cardiopulmonary arrest which occurred in six cases, giving rise to an incidence rate of 1.8%. While apnea occurred quite often, all the patients could be successfully resuscitated. However, one patient suffered neurologic deﬁcits which resolved in a period of 2 weeks. The surgical complications encountered were iridodialyses (four cases) and small cyclodialyses (two cases) with no serious sequelae. Based on their experience of 20 years, the authors believed that goniotomy on two eyes during the same anesthesia is the wisest choice when both eyes require surgery. The life-threatening risk of two anesthetics outweighs the danger of operating on both eyes at the same time. The incidence of endophthalmitis following pediatric anterior segment surgery is currently unknown. The paucity of reports of endophthalmitis has led some observers to recommend simultaneous bilateral surgery for congenital cataracts or glaucoma. Wheeler et al4 surveyed over 500 pediatric ophthalmologists and glaucoma specialists concerning their knowledge on the occurrence of endophthalmitis following pediatric intraocular surgery. Seventeen cases of endophthalmitis were documented to occur out of 24 000 reported surgical cases. This results in an incidence estimate of 0.071% or seven cases per 10 000, which is similar to the reported incidence following extracapsular cataract extraction in adults. In six eyes, endophthalmitis followed goniotomy or trabeculotomy. One patient who underwent bilateral trabeculotomy for congenital glaucoma developed bilateral endophthalmitis leading to no light perception. All other cases

Figure 11.1 Clinical appearance of an infant preoperatively (A) and postoperatively (B) after simultaneous bilateral surgery for congenital glaucoma.

A B

77

Simultaneous surgery for bilateral congenital glaucoma followed unilateral surgery. To our knowledge this is the only reported study on endophthalmitis following antiglaucoma surgery in children with congenital glaucoma.

Anesthetic risks The risks of general anesthesia in infants is still a major concern for congenital glaucoma surgery. Despite major advances in anesthesia in the last few decades, pediatric morbidity and mortality related to anesthesia is still a perplexing problem. In this respect, infants differ more from children than children differ from adults.5 In a recent prospective study, Tiret et al6 reported that the overall complication rate was much higher in infants (43 per 10 000) than in older children (5 per 10 000). In infants, the complications were mostly due to respiratory problems, while circulatory problems were more frequent in older children. It has been pointed out, however, that most cardiac arrests are due to unrecognized hypoxemia.7 Respiratory failure during anesthesia is the major risk factor in infants, the age group in whom congenital glaucoma surgery is the most urgent. This risk increases if additional factors including a history of previous anesthesia,5 intubation,8 and an upper respiratory infection are present preoperatively.9 In addition, anesthesia increases the risk for an upper respiratory infection.10 Smith found a mortality rate of 1.4 per 10 000 in a study covering over 100 000 surgeries in one institution over a 24-year period.11 During the ﬁrst 10 years, infants up to 1 year had an anesthesia-related mortality rate of 8 per 10 000, whereas a lower rate was found for children from 1 to 10 years (1 per 10 000). There are many conditions associated with congenital or infantile cataracts and glaucoma in which anesthetic difﬁculties are higher than average.12 Although formal studies are lacking comparing the risks of more than one induction and extubation with those of prolonged anesthesia time, most anesthesiologists believe that the former is riskier than the latter.

Simultaneous bilateral surgery Recently, there have been reports of simultaneous surgery for bilateral congenital cataracts.13,14 Guo et al13 reported on the results of 16 children (32 eyes) who had simultaneous surgery for bilateral congenital cataracts, and concluded that bilateral simultaneous surgery can be performed to avoid a second general anesthesia in infants with bilateral dense congenital cataracts. In 1996, Zwaan14 reported on a series of nine children (18 eyes) treated with bilateral simultaneous lensectomies. He concluded that simultaneous removal of bilateral infantile cataracts should probably be reserved for selected cases in whom the anesthetic risks are higher than average. Most of the pediatric ophthalmologists have strongly opposed simultaneous bilateral surgeries because of the risk of bilateral endophthalmitis. Endophthalmitis after cataract surgery in adults and children is uncommon. The risk of 78

endophthalmitis in adults varies in several published reports, a summary of which places the overall incidence at 0.35%.15 The occurrence of endophthalmitis after intraocular surgery in infants has been reported. Good et al16 in 1990 documented endophthalmitis after cataract surgery in children, which argues against simultaneous bilateral surgery. A short time delay between operated eyes should not signiﬁcantly affect visual outcome. Kushner17 also believes that it is safer to perform two separate surgical procedures in infants with bilateral cataracts. There are several reports of simultaneous bilateral surgeries for senile cataracts.18–26 Hugkulstone et al27 published a respective review of 24 patients who had undergone simultaneous bilateral trabeculectomy over a 6-year period. They reported no striking advantages in performing simultaneous bilateral trabeculectomies in adults, although no patients suffered complications leading to bilateral blindness.

Clinical experience with simultaneous bilateral surgery for developmental glaucoma One hundred and nine consecutive patients underwent planned simultaneous bilateral primary combined trabeculectomy and trabeculotomy were evaluated for intraoperative and postoperative ocular and anesthetic complications.28 The reasons for performing simultaneous bilateral surgeries were bilateral presentation of the disease and the anesthetic risks involved in two surgeries versus one. Success (intraocular pressure <16 mmHg) probabilities were 91%, 88%, and 69% at 1, 2, and 3 years, respectively. The success probability of 69% was maintained up to 6 years of follow-up. A patient with cleared corneas and preserved visual function is shown in Fig. 11.2. There were no major intraoperative complications, and there was no incidence of endophthalmitis or any other sight-threatening complications. Eight eyes developed a shallow anterior chamber, which required reformation in one third of these eyes. Of the anesthetic complications, apnea occurred in 16% of patients, and all were successfully resuscitated. Two children had delayed recovery: one child recovered and one expired. Cardiopulmonary arrest occurred 5 hours postoperatively during feeding in one child who could not be resuscitated. In this series, simultaneous bilateral primary combined trabeculotomy and trabeculectomy was safe and effective for treatment of the ocular condition (developmental glaucoma), obviated the need for second anesthesia with its associated risks, and offered other beneﬁts to the patients and families.28 Simultaneous bilateral surgeries for congenital glaucoma may be planned due to risks associated with repeat anesthesia and an urge to visually rehabilitate the afflicted children as early as possible to prevent stimulus deprivation amblyopia. Additionally, simultaneous surgery is cost effective because it reduces the hospital stay with greater satisfaction of the parents. The treating surgeon has to balance the risk of bilateral endophthalmitis against the reduced risk of one

References prognosis. In cases of bilateral affliction with congenital glaucoma, bilateral primary surgery offers good success rates and also avoids the risks of repeated anesthesia in these tiny patients.

References A

B Figure 11.2 Preoperative (A) and postoperative (B) appearance of a child after simultaneous bilateral surgery for congenital glaucoma. Note resolution of corneal edema.

anesthesia versus two, reduced cost, and the advantages of simultaneous early visual rehabilitation. A clear understanding of these factors is mandatory for the treating physician as well as the parents.

Conclusion The data in the literature are inadequate for a formal comparison of the risks involved in multiple anesthetics and the possibility of bilateral endophthalmitis. It is therefore prudent to restrict simultaneous bilateral surgeries to infants with an increased vulnerability to anesthetic complications, mostly respiratory failure. However, bilateral simultaneous surgery may expedite treatment and minimize costs, while avoiding the risk of administration of two anesthetics when both eyes are treated with one general anesthesia session. Parents should participate fully in the decision-making process and should understand the risks of possible bilateral endophthalmitis. Utmost care should be taken to eliminate the risks of infection. The afflicted children should be carefully checked for evidence of conjunctivitis, nasolacrimal duct obstruction, or upper respiratory tract infections. The second eye should be prepped and draped as if it were a new case. The surgeon and scrub nurse should re-scrub and use new gowns and gloves. An entirely different set of instruments must be used. The key to successful management of the children afflicted with developmental glaucoma is accurate and early diagnosis coupled with prompt therapy. The earlier any glaucoma is diagnosed and brought under control, the better the

1. deLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19. 2. Hoskins HD, Shaffer RN. Evaluation techniques for congenital glaucoma. J Pediatr Ophthalmol Strabismus 1971; 8:81–87. 3. Litinsky SM, Shaffer RN, Hetherington J, Hoskins HD. Operative complications of goniotomy. Trans Am Ophthalmol Otolaryngol 1977; 83:78–79. 4. Wheeler DT, Stager DR, Weakley DR Jr. Endophthalmitis following pediatric intraocular surgery for congenital cataracts and congenital glaucoma. J Pediatr Ophthalmol Strabismus 1992; 29:139–141. 5. SaintMaurice C. Paediatric anaesthesia. Curr Opin Anaesthesiol 1994; 7:249–250. 6. Tiret L, Nivoche Y, Hatton R, Desmonts JM, Vourch G. Complications related to anesthesia in infants and children: a prospective survey of 40 240 anaesthetics. Br J Anaesthesiol 1988; 61:263–269. 7. Keenan RL, Boyan CP. Cardiac arrest during anesthesia: a study of incidence and causes. JAMA 1985; 253:2373–2377. 8. Laycock GJ, McNicol LR. Hypoxaemia during recovery from anaesthesia: an audit of children after general anaethesia for routine elective surgery. Anesthesiology 1988; 43:985–987. 9. Cohen MM, Cameron CB. Should you cancel the operation when a child has an upper respiratory tract infection? Anesth Analg 1991; 72:282–288. 10. Tait AR, Knight PR. The effects of general anesthesia on upper respiratory tract infections in children. Anesthesiology 1987; 67:930–935. 11. Smith RM. Mortality in pediatric surgery and anesthesia. In: Smith RM, ed. Anesthesia for infants and children, 4th edn. Mosby: St Louis; 1980:653–661. 12. France NK. Ophthalmological diseases. In: Katz J, Steward DJ, eds. Anesthesia and uncommon pediatric disease. WB Saunders: Philadephia, PA; 1987:271–298. 13. Guo S, Nelson LB, Calhoun J, Levin A. Simultaneous surgery for bilateral congenital cataracts. J Pediatr Ophthalmol Strabismus 1990; 27:23–25. 14. Zwaan J. Simultaneous surgery for bilateral pediatric cataracts. Ophthalmic Surg Lasers 1996; 27:15–20. 15. Jaffe NJ. Cataract surgery and its complications. CV Mosby: St Louis; 1990:499. 16. Good WV, King S, Irvine AR, Hoyt CL, Taylor DSI. Postoperative endophthalmitis in children following cataract surgery. J Pediatr Ophthalmol Strabismus 1990; 27:283–285. 17. Kushner BJ. Simultaneous surgery for bilateral congenital cataracts (discussion). J Pediatr Ophthalmol Strabismus 1990; 27:26–27. 18. Duthie OM. Bilateral cataract extraction. Trans Ophthalmol Soc UK 1955; 75:25–31. 19. Akingbehin T, Sunderraj P. Simultaneous bilateral lens implantation: is the procedure justiﬁed? Eur J Implant Refract Surg 1992; 3:131–133. 20. Harﬁtt R, Moriarty A, Mastellone G. Is simultaneous bilateral cataract extraction with lens implantation justiﬁed? Eur J Implant Refract Surg 1992; 3:134–137. 21. Adhikary HP, Harrington L. Simultaneous bilateral intraocular lens implantation. Eur J Implant Refract Surg 1992; 3:138–139. 22. Nielsen PJ. Simultaneous bilateral cataract extraction: ECCE versus ICCE. Eur J Implant Refract Surg 1992; 3:140–144. 23. Joseph N, David R. Bilateral cataract in one session: report on ﬁve years experience. Br J Ophthalmol 1977; 61:619–621. 24. Fenton PJ, Gardner ID. Simultaneous bilateral intraocular surgery. Trans Ophthalmol Soc UK 1982; 102:298–301. 25. Jardine P. Simultaneous bilateral cataract extraction. Trans Ophthalmol Soc UK 1970; 70:719–724. 26. Shepard DD. Are there any indications for simultaneous bilateral cataract– intraocular lens (IOL) surgery? J Cataract Refract Surg 1988; 14:339–345. 27. Hugkulstone CE, Stevenson L, Vernon SA. Simultaneous bilateral trabeculectomy. Eye 1994; 8:398–401. 28. Mandal AK, Bhatia PG, Gothwal VK, et al. Safety and efﬁcacy of simultaneous bilateral primary combined trabeculotomy-trabeculectomy for developmental glaucoma. Indian J Ophthalmol 2002; 50:13–19.

79

Chapter 12 Management of refractory pediatric glaucoma Introduction Filtration surgery with antifibrosis drugs Glaucoma drainage implants Cyclodestructive procedures Laser therapy Conclusions

Introduction Surgical treatment is usually required for developmental glaucoma, using goniotomy or trabeculotomy as primary surgical therapy. Both of these procedures have a high success rate, are equally effective as initial surgical treatment, and have been assessed in large numbers of patients over long periods of time.1,2 However, at least 10% to 20% of patients fail the initial surgical procedure for congenital glaucoma, and some patients have glaucomas with a poor prognosis for the success of initial goniotomy or trabeculotomy. When the intraocular pressure is not controlled after primary surgery, the next step varies according to individual patient factors and surgeon preferences. The surgical options available to treat these children include ﬁltering surgery, glaucoma drainage implants, and cyclodestructive procedures.

Filtration surgery with antifibrosis drugs Children or young adults undergoing ﬁltering surgery do not enjoy the same success rate compared with older age groups. The barriers to success of ﬁltering surgery in children include a thick and active Tenon’s capsule, rapid wound healing response, lower scleral rigidity, and a large buphthalmic eye

with thin sclera.3 Additionally, conjunctival scarring from previous ocular surgery may limit the success of repeat surgery in children with congenital glaucoma. Trabeculectomy without antiﬁbrosis drugs in young patients has been unsuccessful in most,3–6 but not all,7 reports. Antiﬁbrosis drugs have been widely used in adult glaucoma ﬁltering surgery to improve the success rate and produce lower mean postoperative intraocular pressures. The initial experience with antiﬁbrosis drugs as adjunctive treatment for trabeculectomy was with postoperative subconjunctival 5-fluorouracil (5-FU) injections. Adjunctive use of 5-FU has been described in young patients, with some success in achieving intraocular pressure levels in the low teens.8,9 However, 5-FU has disadvantages, including the need for multiple subconjunctival injections (requiring multiple general anesthesias in children) and the possibility of ocular complications such as hypotony and recalcitrant corneal epithelial defects. Also, a small, prospective, randomized trial showed that 5-FU was less effective compared with mitomycin-C in achieving successful control of intraocular pressure in pediatric ﬁltration surgery.10 Mitomycin-C has emerged as an effective antimetabolite for topical use during trabeculectomy (Fig. 12.1). It is an antineoplastic antibiotic isolated from the fermentation ﬁltrate of Streptomyces caespitosus, which has the ability to signiﬁcantly suppress ﬁbrosis and vascular ingrowth after intraoperative application at the site of ﬁltration surgery. Mitomycin-C is a more potent antiﬁbrosis drug compared with 5-FU. In adults, eyes treated with mitomycin-C have lower mean intraocular pressure on fewer medications compared with eyes treated with 5-FU. Also, mitomycin-C is administered in a single intraoperative application, which is more convenient for the patient and surgeon compared with 5-FU.

Figure 12.1 Trabeculectomy with mitomycin-C. This child had been treated previously with trabeculectomy without adjunctive antifibrosis treatment, which had failed to control the intraocular pressure (A). The postoperative appearance shows the characteristic thin-walled, avascular bleb after trabeculectomy with mitomycin-C (B).

A

B

81

Management of refractory pediatric glaucoma

Table 12.1 Studies of trabeculectomy with adjunctive mitomycin-C in children Author, year

MMC procedure

Success criteria

Success %

Susanna et al, 199511

No. eyes 79

0.2 mg/ml, 5 min

IOP ) 21 mmHg

67%

Mandal et al, 199712

19

0.4 mg/ml, 3 min

IOP < 21 mmHg

95%

Agarwal et al, 199713

30

0.2 mg/ml, 4 min 0.4 mg/ml, 4 min

IOP < 21 mmHg without meds

60% 87%

Beck et al, 199514

60

0.25 or 0.5 mg/ml, 5 min

IOP ) 22 mmHg without meds

67%

0.2 to 0.4 mg/ml, 2 to 5 min

IOP ) 21 mmHg without meds

48–85%

Al-Hazmi et al, 199815

254

Mullaney et al, 199916

100

0.2 to 0.4 mg/ml, 2 to 5 min

IOP < 21 mmHg

67%

Azuara-Blanco et al, 199917

21

0.4 mg/ml, 1–5 min

IOP < 21 mmHg without meds

76%

Mandal et al, 199918

38

0.4 mg/ml, 3 min

IOP < 21 mmHg

65%

Freedman et al, 199919

21

0.4 mg/ml, 3–5 min

IOP = 4–16 mmHg

52%

Sidoti et al, 200020

29

0.5 mg/ml, 1.5–5 min

IOP ) 21 mmHg without meds

82–95%

MMC = mitomycin-C, IOP = intraocular pressure, meds = glaucoma medications

Studies of trabeculectomy with adjunctive mitomycin-C in pediatric patients are summarized in Table 12.1.11–20 The success rate reported in these studies ranged from 48% to 95%, depending on the patient’s age, the deﬁnition of success, length of follow-up, and other factors. It is clear that trabeculectomy with mitomycin-C has a higher success rate than trabeculectomy alone in pediatric patients. However, complications were reported in these studies, including hypotony with shallow anterior chamber, choroidal detachment, retinal detachment, cataract, bleb leak, and bleb-related infection (blebitis and endophthalmitis). Sidoti and coworkers20 showed a high (17%) long-term incidence of bleb-related infection in children after trabeculectomy with mitomycin-C. Late bleb-related ocular infection and vision loss may occur in children after trabeculectomy with mitomycin-C.21,22 These infections are characterized by abrupt onset, bleb inﬁltration, and rapid progression (Fig. 12.2). In one report, Staphylococcus grew in three of three eyes that developed bleb-related ocular infection.21 In another report, surgical technique in young patients using a limbus-based conjunctival flap was more likely to result in cystic bleb appearance

Figure 12.2 Late bleb-related infection after trabeculectomy with mitomycin-C. The patient developed blebitis and endophthalmitis associated with a bleb leak several years after trabeculectomy with mitomycin-C. 82

and bleb-related ocular infection compared with a fornix-based conjunctival flap.22 After trabeculectomy with mitomycin-C, patients develop thin-walled, avascular blebs, which may predispose patients to an increased incidence of late complications (Fig. 12.3). Life-long follow-up is required to periodically examine these eyes. The parents of children treated with mitomycin-C-augmented trabeculectomy should be instructed to report to the ophthalmologist on an emergency basis if the operated eye develops redness, discharge, decreased vision, or any other symptoms. The optimal dosing and administration of mitomycin-C in children is yet unknown (Fig. 12.4). Since children are known to have more ﬁbroblastic activity compared to young adults and elderly patients, most clinicians use a standard dose of mitomycin-C, similar to the concentration and exposure time used in elderly patients or young adults. The usual range of concentration used is from 0.2 to 0.4 mg/ml, with an exposure time of 2 to 4 minutes. In adults, no deﬁnite differences in efﬁcacy or success rate have been identiﬁed in this dose range.23,24 Further information would be helpful about the effects of dosing and administration of mitomycin-C on efﬁcacy and adverse effects in pediatric patients. Despite achieving good results with the use of mitomycinC with trabeculectomy, we do not recommend its use during primary surgery in children afflicted with congenital glaucomas. Adjunctive use of mitomycin-C is associated with potentially serious ocular complications and the long-term effects of mitomycin-C are not yet known. Additionally, conventional primary surgery such as goniotomy, trabeculotomy, or combined trabeculotomy–trabeculectomy has been very effective in this patient population. However, intraoperative application of mitomycin-C is a useful option in children with refractory congenital glaucoma with previously failed primary surgery. After trabeculectomy with mitomycin-C, children require periodic examination and the parents should be educated about the possible late complications.

Glaucoma drainage implants

A

B

C

D

Figure 12.3 Overfiltration and hypotony maculopathy after trabeculectomy with mitomycin-C. This 20-year-old male with a history of congenital glaucoma developed hypotony and decreased vision several years after trabeculectomy with mitomycin-C (A). The bleb was elevated, thin-walled, large, and avascular (B). Examination of the retina showed retinal edema and folds consistent with hypotony maculopathy (C). At bleb revision, a scleral patch graft was placed over the melted trabeculectomy flap and sclerostomy, the avascular area of conjunctiva was excised, and the remaining conjunctiva was advanced. Postoperatively (6 weeks), the hypotony resolved, the bleb was elevated, and the vision returned to baseline level (D).

0.4 mg/ml, 4–5 min 0.4 mg/ml, 2–3 min 0.2 mg/ml, 4–5 min 0.2 mg/ml, 2–3 min 0

20

40 60 Percent success

80

100

Figure 12.4 Surgical success with varying applications of mitomycin-C. In this series of 254 eyes with developmental glaucoma, surgical success was defined as postoperative intraocular pressure greater than 3 mmHg and less than 21 mmHg without additional medications or surgery, at least one year after surgery. Comparisons between these groups showed no statistically significant differences. From data in Al-Hazmi A, Zwaan J, Awad A, et al. Effectiveness and complications of mitomycin-C use during pediatric glaucoma surgery. Ophthalmology 1998; 105:1915–1920.

Glaucoma drainage implants Glaucoma drainage implants are useful when other surgical treatments have a poor prognosis for success, prior conventional surgery fails, or when signiﬁcant conjunctival scarring precludes ﬁltration surgery (Fig. 12.5). Smaller sized drainage implants have been marketed for use in pediatric patients, but adult sized devices are commonly implanted. Available types of drainage implants may be characterized as open tube (non-restrictive) devices or valved (flow-restrictive) devices. Examples of open tube implants include the Molteno and Baerveldt implants, whereas the Krupin implant and the Ahmed Glaucoma Valve are flow-restrictive devices. The flowrestrictive devices are intended to reduce the incidence of

Figure 12.5 Glaucoma drainage implant tube in the anterior chamber of an 11-year-old with a history of congenital glaucoma. This child had failed primary surgery and had significant conjunctival scarring. There are Haab’s striae in the cornea.

complications associated with hypotony during the immediate postoperative period. Glaucoma drainage implants are most commonly placed in the superotemporal quadrant, but may be surgically positioned in any quadrant. Studies of glaucoma drainage implants in pediatric patients are summarized in Table 12.2.25–42 The success rate reported in these studies ranged from 56% to 95%, depending on the patient age, the deﬁnition of success, length of follow-up, and other factors (Figs 12.6 and 12.7). Glaucoma drainage implants may be effective in controlling the intraocular pressure, even in pediatric patients who have failed previous glaucoma surgery. However, complications have been associated with glaucoma drainage implants in pediatric patients. Reported complications include hypotony with shallow anterior chamber and choroidal detachments, tube–cornea touch and corneal edema, obstructed tube, exposed tube or plate, endophthalmitis, and retinal detachment. Most of these complications did not affect outcomes, but a small proportion were associated with vision loss. 83

Management of refractory pediatric glaucoma

Table 12.2 Studies of glaucoma drainage implants in pediatric patients Author, year

No. eyes

Molteno et al, 1984

25

Billson et al, 198926 Hill et al, 1991

27

Implant type

Success criteria

Success %

83

Molteno

IOP < 20 mmHg no meds IOP < 20 mmHg ± meds

73% 95%

23

Molteno

IOP < 21 mmHg ± meds

78%

65

Molteno

5 mmHg < IOP < 22 mmHg

62%

Munoz et al, 199128

53

Molteno

IOP < 22 mmHg

68%

Lloyd et al, 199229

16

Molteno

5 mmHg < IOP < 22 mmHg

56%

Nesher et al, 199230

27

Molteno

IOP ) 21 mmHg ± meds

57%

Netland & Walton, 1993

20

Molteno, Baerveldt

IOP ) 21 mmHg

80%

Fellenbaum et al, 199532

30

Baerveldt

5 mmHg < IOP < 22 mmHg

86%

Siegner et al, 199533

15

Baerveldt

5 mmHg < IOP < 22 mmHg

80%

Coleman et al, 199734

24

Ahmed

IOP < 22 mmHg 1 year: 2 year:

78% 61%

31

Eid et al, 199735

18

Molteno, Schocket, Baerveldt

6 mmHg < IOP < 21 mmHg

72%

Donahue et al, 199736

23

Baerveldt

IOP < 21 mmHg ± meds

61%

Huang et al, 199937

11

Ahmed

5 mmHg < IOP < 22 mmHg

91%

Englert et al, 199938

27

Ahmed

IOP < 22 mmHg

85%

35

Ahmed

IOP < 22 mmHg 1 year: 2 year:

70% 64%

Djodeyre et al, 2001

39

Pereira et al, 200240

10

Krupin, Schocket, Molteno, Baerveldt

IOP < 22 mmHg

80%

Morad et al, 200341

60

Ahmed

IOP < 21 mmHg 1 year: 2 year:

93% 86%

5 mmHg ) IOP < 22 mmHg 1 year: 2 year

80% 67%

Budenz et al, 200442

62

Baerveldt

100

100

80

80

% Success

% Success

IOP = intraocular pressure, meds = glaucoma medications, NS = not specified

60 40 20 0

40 20

0

5

10

15

20 Months

25

30

35

40

Figure 12.6 Percent success after Molteno and Baerveldt implants in pediatric patients. Success was defined as intraocular pressure of 21 mmHg or less without further surgical therapy. The overall success was 80%. Modified with permission from Netland PA, Walton DS. Glaucoma drainage implants in pediatric patients. Ophthalmic Surg 1993; 24:723–729 (reference 31).

84

60

0

0

6

12

18 Months

24

30

36

Figure 12.7 Percent success after Ahmed Glaucoma Valve in pediatric patients. Success was defined as an average intraocular pressure less than 22 mmHg (or lowered by at least 20% from preoperative values in eyes with preoperative intraocular pressure less than 22 mmHg) and no additional glaucoma surgeries or visually devastating complications. The cumulative probability of success was 78% at 12 months. Data from Coleman AL, Smyth RJ, Wilson MR, Tam M. Initial clinical experience with the Ahmed Glaucoma Valve implant in pediatric patients. Arch Ophthalmol 1997; 115:186–191 (reference 34).

Cyclodestructive procedures

IOP (mmHg) Medications

Intraocular pressure

30 25

2.5 2.0

20

1.5

15

1.0

10

0.5

5 0

3.0

0

5

10 Time (months)

15

Number of medications

35

0.0 20

Figure 12.8 Mean intraocular pressure (mmHg) and number of medications after implantation of Ahmed Glaucoma Valve in pediatric patients with refractory glaucoma. By 3 months postoperatively, the intraocular pressure and number of medications had become stable. From data in Englert J, Freedman SF, Cox TA. The Ahmed Valve in refractory pediatric glaucoma. Am J Ophthalmol 1999; 127:34–42.

Postoperatively, patients often require adjunctive glaucoma medications and close monitoring for complications (Fig. 12.8). Iris creep around the tube insertion site may cause corectopia with drainage implants in children.43 Extraocular muscle imbalance has been reported after Baerveldt implant,44 but this may occur after any type of drainage implant. Conjunctival and even transcorneal45 tube erosions have been reported in children, which may lead to delayed endophthalmitis.46,47 Episodes of postoperative hypotony are commonly reported with open-tube implants, whereas the flow-resistive implants have reduced rate of hypotony in the immediate postoperative period. Two-stage implantation of a glaucoma drainage device may be considered for eyes at high risk for complications due to hypotony.25,26 In the ﬁrst stage, the plate is implanted and the tube is left under the conjunctiva near the limbus. A period of 4 to 6 weeks prior to the second stage allows a pseudocapsule to form, which provides some resistance to aqueous flow in the immediate postoperative period after tube insertion. In the second stage, the tube is inserted into the anterior chamber. This approach is most commonly used for open tube implants, such as the Molteno25,26 and Baerveldt48 implants, but may also be used for flow-resistive valves. Glaucoma associated with Sturge–Weber syndrome may be due to isolated trabeculodysgenesis or to elevated episcleral venous pressure, which predisposes these patients to flat anterior chamber and choroidal detachment after glaucoma surgery. Goniotomy or trabeculotomy often fail, but these procedures are preferred as primary surgery, because of a lower complication rate compared with trabeculectomy.49 Glaucoma drainage implants have been helpful in patients with Sturge–Weber syndrome requiring additional surgical treatment. Satisfactory results have been reported using a two-stage Baerveldt implant48 or a single stage Ahmed Glaucoma Valve.50

If the intraocular pressure increases after glaucoma drainage implant, most clinicians will recommend adjunctive medical therapy. If adjunctive medical therapy fails to control the intraocular pressure, supplemental laser cyclophotocoagulation may be very useful.51 Another alternative is revision of the drainage implant, excising a portion of the pseudocapsule around the implant plate.52 This approach is similar in concept to needling of encapsulated blebs, and has a similar success rate. Additional glaucoma drainage devices may be implanted in an unused quadrant, which may control the intraocular pressure.53,54 In the 10–20% of patients who fail initial surgery for developmental glaucoma, the clinician often chooses trabeculectomy with mitomycin-C or a drainage implant as a subsequent surgical treatment. In one study comparing outcomes of trabeculectomy with mitomycin-C and glaucoma drainage implant, the success rate was higher after drainage implant,55 whereas another study found similar success rates after these two procedures.56 Both procedures are useful in patients with developmental glaucoma that is refractory to initial surgical treatment. We often proceed to trabeculectomy with mitomycin-C after failed primary surgery and, if this procedure is unsuccessful, drainage implant is indicated. However, the exact order of treatment is dependent on individual surgeon preference at this time.

Cyclodestructive procedures After initial and secondary surgical treatments fail to control the intraocular pressure, a cyclodestructive procedure may be considered. In some instances, these treatments may be performed as adjunctive therapy or as primary therapy. Cyclodestructive procedures cause damage to the ciliary epithelium, reduce aqueous production, and thereby lower the intraocular pressure. The most commonly performed procedures include cyclocryotherapy and cyclophotocoagulation. When available, cyclophotocoagulation is usually the preferred procedure because it is associated with less postoperative inflammation and less discomfort for the patient compared with cyclocryotherapy. In cyclodestructive procedures, the amount of treatment required to achieve the desired degree of intraocular pressure reduction may be difﬁcult to titrate.57 Retreatments are often necessary after cyclodestructive procedures. Perhaps most importantly, these procedures may be associated with visionthreatening complications. The risk of hypotony, vision loss, and even phthisis is substantial. Parents should be informed about these possibilities and patients should be monitored for these problems. In cyclocryotherapy, a probe is applied just posterior to the limbus to freeze the ciliary body and ciliary epithelium. Al Faran and coworkers58 reported a 30% success rate, with no difference between the success rates in eyes that been treated with other glaucoma procedures prior to cyclocryotherapy compared with eyes with no previous glaucoma surgery. Wagle and coworkers59 reported 44% success after cyclocryotherapy in refractory pediatric glaucoma, requiring an

85

Management of refractory pediatric glaucoma 100

% Success

80 60 40 20 0

0

2

4

6 Years

8

10

12

Figure 12.9 Long-term success rate after cyclocryotherapy for refractory pediatric glaucoma. Success was defined as intraocular pressure of 21 mmHg or less without devastating complications or need for further glaucoma surgery. The overall success at last follow-up visit was 44%. The life-table analysis showed cumulative probability of success declining to 36% with extended follow-up. Modified with permission from Wagle NS, Freedman SF, Buckley EG, Davis JS, Biglan AW. Long-term outcome of cyclocryotherapy for refractory pediatric glaucoma. Ophthalmology 1998; 105:1921–1927.

average of 4.1 treatments for successful eyes (Fig. 12.9). Devastating complications occurred even more frequently among eyes with aniridia compared with other eyes (50% and 11%, respectively). Vision-threatening complications include retinal detachment, hypotony, and phthisis. Cyclophotocoagulation can be performed with a variety of lasers, including the neodymium:yttrium–aluminum–garnet (Nd:YAG), 810 nm diode, and krypton laser (Fig. 12.10). Although non-contact procedures have been described, the procedure is usually performed with a specially designed contact probe, which is applied near the limbus over the ciliary body. In children, the procedure is usually performed under general anesthesia in the supine position. Table 12.3 summarizes the results of studies of cyclophotocoagulation in pediatric patients.60–66 In general, success rates with a single treatment are low, retreatment is often required, and complications are perhaps less frequent but are similar to those found after cyclocryotherapy.

Figure 12.10 Cyclophotocoagulation. The diode laser handpiece attachment from one manufacturer is shown. The ciliary body is treated with the laser, which reduces aqueous production. Modified from figure provided courtesy of Iris Medical.

Cyclophotocoagulation may be performed with an endolaser and an endoscope, although this approach is not widely available. The procedure requires intraocular surgery, but the laser energy is delivered more precisely to the target tissue.67–70 In a study of 36 eyes, Neely and Plager69 reported a success rate of the initial procedure of 34% (intraocular pressure ) 21 mmHg, with or without adjunctive glaucoma medications), which increased to 43% after retreatments. At this time, there is no clear beneﬁt of this procedure compared with contact transscleral cyclophotocoagulation. Cyclodestructive procedures are usually reserved for children who have not responded to other surgical treatments for intractable elevation of intraocular pressure. These procedures have limited success rates, often require retreatment, and may be associated with vision-threatening complications. Some clinicians advocate cyclodestructive procedures

Table 12.3 Studies of contact transscleral cyclophotocoagulation in pediatric patients Author, year

No. eyes

Laser

Success criteria

Success %

Phelan & Higginbotham, 199560

10

Nd:YAG

IOP < 21 mmHg

50%

Bock et al, 199761

26

Diode

IOP ) 21 mmHg

38% 50%*

Hamard et al, 200062

28

Diode

6 mmHg < IOP < 20 mmHg

28%*

Izgi et al, 200163

41

Diode

IOP < 22 mmHg

59% 75%*

Raivio et al, 200164

27

Krypton

8 mmHg ) IOP ) 21 mmHg

64%*

Kirwin et al, 200265

77

Diode

IOP < 22 mmHg

37% 72%*

Autrata & Rehurek, 200366

69

Diode

IOP ) 21 mmHg

41% 79%*

*Success rate allowing retreatment. Nd:YAG, neodymium:yttrium–aluminum–garnet; IOP, intraocular pressure; NS, not specified.

86

References early in the surgical treatment regimen, while most reserve cycloablation until after other primary and secondary treatments have failed. Supplemental sub-maximal or full treatment with cyclophotocoagulation may be useful if the intraocular pressure is uncontrolled despite glaucoma drainage implants or other glaucoma surgical treatments.51

Laser therapy With the exception of laser cyclophotocoagulation, there is a limited role for laser therapy in the treatment of pediatric glaucomas. Although angle-closure may occur in children,71–74 surgical iridectomy is usually performed. Children require general anesthesia for both laser and surgical iridectomy, and the logistics of laser treatment may be difﬁcult. Laser trabeculoplasty is the most commonly performed laser procedure for open-angle glaucoma in adults, but this procedure is not useful in children. Nd:YAG goniopuncture has been tried in young patients;75,76 however, the long-term success is poor.

Conclusions Patients with congenital glaucoma may fail the initial surgical procedure, and some pediatric patients have glaucomas with a poor prognosis for the success of initial goniotomy or trabeculotomy. Trabeculectomy alone has a poor long-term success rate, but trabeculectomy with adjunctive antiﬁbrosis drug (e.g., mitomycin-C) has a satisfactory success rate. Patients, however, may develop late complications and require continued monitoring for problems such as bleb leak and bleb-related infections. Glaucoma drainage device implantation is another useful option in these patients. Patients often require adjunctive glaucoma medications and may develop complications, most of which are not visionthreatening. Cyclodestructive procedures may be useful, especially in children with elevated intraocular pressure despite previous trabeculectomy or glaucoma drainage implant.

References 1. Anderson DR. Trabeculotomy compared to goniotomy for glaucoma in children. Ophthalmology 1983; 90:805–806. 2. Shaffer RN. Prognosis of goniotomy in primary infantile glaucoma (trabeculodysgenesis). Trans Am Ophthalmol Soc 1982; 80:321–325. 3. Beauchamp GR, Parks MM. Filtering surgery in children: barriers to success. Ophthalmology 1979; 86:170–180. 4. Cadera W, Pachtman MA, Cantor LB, et al. Filtering surgery in childhood glaucoma. Ophthalmic Surg 1984; 15:319–322. 5. Gressel MG, Heuer DK, Parrish RK II. Trabeculectomy in young patients. Ophthalmology 1984; 91:1242–1246. 6. Veldman E, Greve EL. Glaucoma ﬁltering surgery, a retrospective study of 300 operations. Doc Ophthalmol 1987; 67:151–170. 7. Burke JP, Bowell R. Primary trabeculectomy in congenital glaucoma. Br J Ophthalmol 1989; 73:186–190. 8. Zalish M, Leiba H, Oliver M. Subconjunctival injection of 5-fluorouracil following trabeculectomy for congenital and infantile glaucoma. Ophthalmic Surg 1992; 23:203–205. 9. Michel JW, Liebmann JM, Ritch R. Initial 5-fluorouracil trabeculectomy in young patients. Ophthalmology 1992; 99:7–13. 10. Snir M, Lusky M, Shalev B, Gaton D, Weinberger D. Mitomycin-C and 5-fluorouracil antimetabolite therapy for pediatric glaucoma ﬁltration surgery. Ophthalmic Surg Lasers 2000; 31:31–37.

11. Susanna R Jr, Oltrogge EW, Carani JCE, Nicolela MT. Mitomycin as adjunct chemotherapy with trabeculectomy in congenital and developmental glaucomas. J Glaucoma 1995; 4:151–157. 12. Mandal AK, Walton DS, John T, Jayagandan A. Mitomycin-C-augmented trabeculectomy in refractory congenital glaucoma. Ophthalmology 1997; 104:996–1001. 13. Agarwal HC, Sood NN, Sihota R, Sanga L, Honavar SG. Mitomycin-C in congenital glaucoma. Ophthalmic Surg Lasers 1997; 28:979–985. 14. Beck AD, Wilson WR, Lynch MG, Lynn MJ, Noe R. Trabeculectomy with adjunctive mitomycin-C in pediatric glaucoma. Am J Ophthalmol 1998; 126:648–657. 15. Al-Hazmi A, Zwaan J, Awad A, et al. Effectiveness and complications of mitomycin-C use during pediatric glaucoma surgery. Ophthalmology 1998; 105:1915–1920. 16. Mullaney PB, Selleck C, Al-Awad A, Al-Mesfer S, Zwaan J. Combined trabeculotomy and trabeculectomy as an initial procedure in uncomplicated congenital glaucoma. Arch Ophthalmol 1999; 117:457–460. 17. Azuara-Blanco A, Wilson RP, Spaeth GL, Schmidt CM, Augsburger JJ. Filtration procedures supplemented with mitomycin-C in the management of childhood glaucomas. Br J Ophthalmol 1999; 83:151–156. 18. Mandal AK, Prasad K, Naduvilath TJ. Surgical results and complications of mitomycin-C-augmented trabeculectomy in refractory developmental glaucoma. Ophthalmic Surg Lasers 1999; 30:473–480. 19. Freedman SF, McCormick K, Cox TA. Mitomycin-C-augmented trabeculectomy with postoperative wound modulation in pediatric glaucoma. J AAPOS 1999; 3:117–124. 20. Sidoti PA, Belmonte SJ, Liebmann JM, Ritch R. Trabeculectomy with mitomycin-C in the treatment of pediatric glaucomas. Ophthalmology 2000; 107:422–429. 21. Waheed S, Ritterband DC, Greenﬁeld DS, et al. Bleb-related ocular infection in children after trabeculectomy with mitomycin-C. Ophthalmology 1997; 104:2117–2120. 22. Wells AP, Cordeiro MF, Bunce C, Khaw PT. Cystic bleb formation and related complications in limbus- versus fornix-based conjunctival flaps in pediatric and young adult trabeculectomy with mitomycin-C. Ophthalmology 2003; 110:2192–2197. 23. Megevand GS, Salmon JF, Scholtz RP, et al. The effect of reducing the exposure time of mitomycin-C in glaucoma ﬁltering surgery. Ophthalmology 1995; 102:84–90. 24. Lee JJ, Park KH, Youn DH. The effect of low- and high-dose adjunctive mitomycin-C in trabeculectomy. Korean J Ophthalmol 1996; 10:42–47. 25. Molteno AC, Ancker E, Van Biljon G. Surgical technique for advanced juvenile glaucoma. Arch Ophthalmol 1984; 12:51–57. 26. Billson F, Thomas R, Aylward W. The use of two-stage Molteno implants in developmental glaucoma. J Pediatr Ophthalmol Strabismus 1989; 26:3–8. 27. Hill RA, Heuer DK, Baerveldt G, Minckler DS, Martone JF. Molteno implantation for glaucoma in young patients. Ophthalmology 1991; 98:1042–1046. 28. Munoz M, Tomey KF, Traverso C, Day SH, Senft SH. Clinical experience with the Molteno implant in advanced infantile glaucoma. J Pediatr Ophthalmol Strabismus 1991; 28:68–72. 29. Lloyd MA, Sedlak T, Heuer DK, et al. Clinical experience with the singleplate Molteno implant in complicated glaucomas. Update of a pilot study. Ophthalmology 1992; 99:679–687. 30. Nesher R, Sherwood MB, Kass MA, Hines JL, Kolker AE. Molteno implants in children. J Glaucoma 1992; 1:228–232. 31. Netland PA, Walton DS. Glaucoma drainage implants in pediatric patients. Ophthalmic Surg 1993; 24:723–729. 32. Fellenbaum PS, Sidoti PA, Heuer DK, et al. Experience with the Baerveldt implant in young patients with complicated glaucomas. J Glaucoma 1995; 4:91–97. 33. Siegner SW, Netland PA, Urban RC Jr, et al. Clinical experience with the Baerveldt glaucoma drainage implant. Ophthalmology 1995; 102:1298–1307. 34. Coleman AL, Smyth RJ, Wilson MR, Tam M. Initial clinical experience with the Ahmed Glaucoma Valve implant in pediatric patients. Arch Ophthalmol 1997; 115:186–191. 35. Eid TE, Katz LJ, Spaeth GL, Augsburger JJ. Long-term effects of tube-shunt procedures on management of refractory childhood glaucoma. Ophthalmology 1997; 104:1011–1016. 36. Donahue SP, Keech RV, Munden P, Scott WE. Baerveldt implant surgery in the treatment of advanced childhood glaucoma. J AAPOS 1997; 1:41–45. 37. Huang MC, Netland PA, Coleman AL, et al. Intermediate-term clinical experience with the Ahmed Glaucoma Valve Implant. Am J Ophthalmol 1999; 127:27–33. 38. Englert JA, Freedman SF, Cox TA. The Ahmed valve in refractory pediatric glaucoma. Am J Ophthalmol 1999; 127:34–42.

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Management of refractory pediatric glaucoma 39. Djodeyre MR, Peralta Calvo J, Abelairas Gomez J. Clinical evaluation and risk factors of time to failure of Ahmed Glaucoma Valve implant in pediatric patients. Ophthalmology 2001; 108:614–620. 40. Pereira ML, Araujo SV, Wilson RP, et al. Aqueous shunts for intractable glaucoma in infants. Ophthalmic Surg Lasers 2002; 33:19–29. 41. Morad Y, Donaldson CE, Kim YM, Abdolell M, Levin AV. The Ahmed drainage implant in the treatment of pediatric glaucoma. Am J Ophthalmol 2003; 135:821–829. 42. Budenz DL, Gedde SJ, Brandt JD, Kira D, Feuer W, Larson E. Baerveldt Glaucoma Implant in the management of refractory childhood glaucomas. Ophthalmology 2004; 111:2204–2210. 43. Fuller JR, Molteno AC, Bevin TH. Iris creep producing corectopia in response to Molteno implants. Arch Ophthalmol 2001; 119:304. 44. Smith SL, Starita RJ, Fellman RL, Lynn JR. Early clinical experience with the Baerveldt 350-mm2 glaucoma implant and associated extraocular muscle imbalance. Ophthalmology 1993; 100:914–918. 45. Al-Torbak A, Edward DP. Transcorneal tube erosion of an Ahmed valve implant in a child. Arch Ophthalmol 2001; 119:1558–1559. 46. Al-Torbaq AA, Edward DP. Delayed endophthalmitis in a child following an Ahmed glaucoma valve implant. J AAPOS 2002; 6:123–125. 47. Gedde SJ, Scott IU, Tabandeh H, et al. Late endophthalmitis associated with glaucoma drainage implants. Ophthalmology 2001; 108:1323–1327. 48. Budenz DL, Sakamoto D, Eliezer R, Varma R, Heuer DK. Two-staged Baerveldt glaucoma implant for childhood glaucoma associated with Sturge-Weber syndrome. Ophthalmology 2000; 107:2105–2110. 49. Iwach AG, Hoskins HD Jr, Hetherington J Jr, Shaffer RN. Analysis of surgical and medical management of glaucoma in Sturge-Weber syndrome. Ophthalmology 1990; 97:904–909. 50. Hamush NG, Coleman AL, Wilson MR. Ahmed glaucoma valve implant for management of glaucoma in Sturge-Weber syndrome. Am J Ophthalmol 1999; 128:758–760. 51. Semchyshyn TM, Tsay JC, Joos KM. Supplemental transscleral diode laser cyclophotocoagulation after aqueous shunt placement in refractory glaucoma. Ophthalmology 2002; 109:1078–1084. 52. Tsai JC, Grajewski AL, Parrish RK 2nd. Surgical revision of glaucoma shunt implants. Ophthalmic Surg Lasers 1999; 30:41–46. 53. Shah AA, WuDunn D, Cantor LB. Shunt revision versus additional tube shunt implantation after failed tube shunt surgery in refractory glaucoma. Am J Ophthalmol 2000; 129:455–460. 54. Burgoyne JK, WuDunn D, Lakhani V, Cantor LB. Outcomes of sequential tube shunts in complicated glaucoma. Ophthalmology 2000; 107:309–314. 55. Beck AD, Freedman S, Kammer J, Jin J. Aqueous shunt devices compared with trabeculectomy with mitomycin-C for children in the ﬁrst two years of life. Am J Ophthalmol 2003; 136:994–1000. 56. Hill R, Ohanesian R, Voskanyan L, Malayan A. The Armenian Eye Care Project: surgical outcomes of complicated paediatric glaucoma. Br J Ophthalmol 2003; 87:673–676. 57. Terraciano AJ, Sidoti PA. Management of refractory glaucoma in childhood. Curr Opin Ophthalmol 2002; 13:97–102. 58. Al Faran MF, Tomey KF, Al Mutlaq FA. Cyclocryotherapy in selected cases of congenital glaucoma. Ophthalmic Surg 1990; 21:794–798.

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59. Wagle NS, Freedman SF, Buckley EG, Davis JS, Biglan AW. Long-term outcome of cyclocryotherapy for refractory pediatric glaucoma. Ophthalmology 1998; 105:1921–1926. 60. Phelan MJ, Higginbotham EJ. Contact transscleral Nd:YAG laser cyclophotocoagulation for the treatment of refractory pediatric glaucoma. Ophthalmic Surg Lasers 1995; 26:401–403. 61. Bock CJ, Freedman SF, Buckley EG, Shields MB. Transscleral diode laser cyclophotocoagulation for refractory pediatric glaucomas. J Pediatr Ophthalmol Strabismus 1997; 34:235–239. 62. Hamard P, May F, Quesnot S, Hamard H. Trans-scleral diode laser cyclophotocoagulation for the treatment of refractory pediatric glaucoma. J Fr Ophtalmol 2000; 23:773–780. 63. Izgi B, Demirci H, Demirci FY, Turker G. Diode laser cyclophotocoagulation in refractory glaucoma: comparison between pediatric and adult glaucomas. Ophthalmic Surg Lasers 2001; 32:100–107. 64. Raivio VE, Immonen IJ, Puska PM. Transscleral contact krypton laser cyclophotocoagulation for treatment of glaucoma in children and young adults. Ophthalmology 2001; 108:1801–1807. 65. Kirwin JF, Shah P, Khaw PT. Diode laser cyclophotocoagulation: role in the management of refractory pediatric glaucomas. Ophthalmology 2002; 109:316–323. 66. Autrata R, Rehurek J. Long-term results of transscleral cyclophotocoagulation in refractory pediatric glaucoma patients. Ophthalmologica 2003; 217:393–400. 67. Chen J, Cohn RA, Lin SC, Cortes AE, Alvarado JA. Endoscopic photocoagulation of the ciliary body for treatment of refractory glaucomas. Am J Ophthalmol 1997; 124:787–796. 68. Plager DA, Neely DE. Intermediate-term results of endoscopic diode laser cyclophotocoagulation for pediatric glaucoma. J AAPOS 1999; 3:131–137. 69. Neely DE, Plager DA. Endocyclophotocoagulation for management of difﬁcult pediatric glaucomas. J AAPOS 2001; 5:221–229. 70. Barkana Y, Morad Y, Ben-nun J. Endoscopic photocoagulation of the ciliary body after repeated failure of trans-scleral diode-laser cyclophotocoagulation. Am J Ophthalmol 2002; 133:405–407. 71. Vajpayee RB, Angra SK, Titiyal JS, Sharma YR, Chabbra VK. Pseudophakic pupillary-block glaucoma in children. Am J Ophthalmol 1991; 111:715–718. 72. Michael AJ, Pesin SR, Katz LJ, Tasman WS. Management of late-onset angleclosure glaucoma associated with retinopathy of prematurity. Ophthalmology 1991; 98:1093–1098. 73. Fivgas GD, Beck AD. Angle-closure glaucoma in a 10-year-old girl. Am J Ophthalmol 1997; 124:251–253. 74. Ritch R, Chang BM, Lieberman JM. Angle closure in younger patients. Ophthalmology 2003; 110:1880–1889. 75. Melamed S, Latina MA, Epstein DL. Neodymium:YAG laser trabeculopuncture in juvenile open-angle glaucoma. Ophthalmology 1987; 94:163–170. 76. Senft SH, Tomey KF, Traverso CE. Neodymium–YAG laser goniotomy vs surgical goniotomy. A preliminary study in paired eyes. Arch Ophthalmol 1989; 107:1773–1776.

Chapter 13 Penetrating keratoplasty in children with developmental glaucomas Introduction Penetrating keratoplasty in children with congenital glaucoma Timing of glaucoma surgery Conclusion

Introduction Before the 1970s, there was considerable reluctance to perform penetrating keratoplasty in children. Since that time, reports of successful penetrating keratoplasty in the pediatric age group have appeared. These reports demonstrate that, with modern surgical techniques, corneal opacities can be removed and clear grafts can be maintained in many children. During the last four decades, the age at which a reasonable degree of success can be achieved has decreased from adolescence to young childhood to infancy. However, corneal edema or scarring from developmental glaucoma is a rare indication for penetrating keratoplasty in children. The efﬁcacy of corneal transplantation in infants with corneal opacity secondary to developmental glaucoma has not been established. The aim of this chapter is to provide an overview of penetrating keratoplasty in children with developmental glaucoma. We summarize here the analysis of results, identify the variables that influence the surgical outcome, and offer recommendations for the management of children with corneal opacities secondary to the developmental glaucomas.

Penetrating keratoplasty in children with congenital glaucoma The graft survival and the development of useful vision after penetrating keratoplasty for pediatric congenital glaucoma has varied signiﬁcantly in the literature. In an early case report, Waring and Laibson1 reported one infant with congenital glaucoma associated with hypertrophic vascularized corneal opacity who had ‘travel vision’ in one eye after undergoing three grafts in two eyes. The authors recommended early keratoplasty in patients with bilateral congenital opacities, but did not recommend keratoplasty in children with unilateral corneal opacities. Schanzlin and coworkers2 reported a child with congenital glaucoma, bilateral sclerocornea, and multiple congenital anomalies. During the ﬁrst week of life, the patient had undergone bilateral trabeculotomy. This procedure initially

controlled the intraocular pressure, but eventually the tension was elevated in both eyes. Subsequently, the patient underwent bilateral full-thickness ﬁltering surgery at the second and third months, respectively. When the patient was 6 months old, a 6.5-mm penetrating keratoplasty was performed on the right eye. Intraoperatively, the patient was found to have aniridia, and the lens was adherent to the posterior surface of the cornea, necessitating extracapsular removal of the lens. The graft remained transparent for eight months and the patient, ﬁtted with an aphakic soft contact lens, was able to follow objects. At 8 months postoperatively, an epithelial defect developed that healed after one month, leaving a 2-mm diameter superﬁcial central opacity within an otherwise transparent graft. Stulting and colleagues3 retrospectively studied 91 patients, 14 years of age or less, who had 152 penetrating keratoplasties in 107 eyes, with an average follow-up of 30 months. In this series, there were six eyes with congenital glaucoma and corneal edema. Overall, the graft survival rate at 12 months ranged from 60% among congenitally opaciﬁed eyes to 73% among those with acquired non-traumatic disease. The survival of the grafts in the congenital glaucoma group was not separately analyzed. Frucht-Pery and coworkers4 reported corneal transplantation of congenitally opaque corneas in three children with buphthalmos. The eyes were treated initially with cyclocryotherapy, one application in one eye and two applications in two eyes. The size of the eyes decreased during the ﬁrst two weeks postoperatively. Subsequent corneal transplantation improved vision in each eye, with a visual acuity of 20/400 in one child and formed images in two infants. Huang and colleagues5 reported their experience with eight consecutive penetrating keratoplasties performed in adults with a history of congenital glaucoma. Six grafts remained clear and visual acuity was improved in ﬁve eyes (63%) after penetrating keratoplasty. Postoperative visual acuity was 20/40 (two patients), 20/100 to 20/400 (four patients), counting ﬁngers (one patient) and hand motions (one patient). The most common surgical complication was postoperative elevation of intraocular pressure, which occurred in all the cases (8/8 eyes). The elevated intraocular pressure required treatment with permanent augmentation of glaucoma medications in seven eyes (88%) and glaucoma surgery in four eyes (50%). Two eyes (25%) developed corneal graft failure, one from immune rejection and the other from severe postoperative glaucoma treated with cyclocryotherapy. In view of these complications and the multiple impediments to 89

Penetrating keratoplasty good postoperative vision, the authors concluded that penetrating keratoplasty be reserved for patients with severe visual disability whose preoperative glaucoma is wellcontrolled. Cowden6 analyzed the results of keratoplasty performed in 50 children, with age ranging from 2 months to 14 years, who underwent 66 penetrating keratoplasties. He found that congenital glaucoma patients had the highest percentage of clear grafts (100% in seven cases) compared with any other group of pediatric patients after corneal transplantation. Erlich and coworkers7 reported their experience with corneal transplantation in infants, children, and young adults performed at the Toronto Hospital for Sick Children between 1979 and 1988. Eighty-ﬁve penetrating keratoplasty procedures were performed in 54 patients with age ranging from 1 month to 18 years. Thirteen penetrating keratoplasty procedures were performed in eight patients with congenital glaucoma. Of these eight patients, ﬁve patients (62%) required two procedures. The average age at the time of the ﬁrst procedure was 22.8 months (range from 10 months to 11.7 years). In patients with a history of congenital glaucoma, none of the grafts were clear after the average follow-up period of 16.6 months (range from 3 months to 4 years). The outcome was poor in patients with congenital glaucoma; however, the authors recommended that penetrating keratoplasty may be performed in children with Peters anomaly, herpes simplex keratitis, corneal dystrophy, or traumatic corneal scarring (Fig. 13.1). Ariyasu and coworkers8 retrospectively reviewed the results of nine penetrating keratoplasties performed in eight eyes of six children who had multiple risk factors for poor prognosis. The risk factors included age less than 2 years at the time of grafting, uncontrolled glaucoma, concurrent lensectomy, retinal or glaucoma surgery, aphakia, and acute perforation. Six of the nine grafts (67%) remained clear during a mean follow-up of 24 months (30 months follow-up in eyes with clear grafts). Development of ambulatory vision or better occurred in six of eight (75%) eyes after corneal transplantation and treatment of refractive errors and amblyopia. Graft failure occurred in three eyes: two from graft failure, and one

Figure 13.1 Herpetic keratouveitis associated with elevated intraocular pressure in an adolescent patient. This patient maintained a clear graft, although filtration surgery failed to control the intraocular pressure. A glaucoma drainage implant was successful in controlling the intraocular pressure.

90

from graft rejection. Complications included one case of total retinal detachment, one case of keratitis due to Streptococcus pneumoniae, and three cases of elevated intraocular pressure requiring further glaucoma surgery. The authors concluded that useful vision can be achieved after penetrating keratoplasty even in some high-risk infants with congenital glaucoma. Dana and coworkers9 reported the results of a multicenter study to delineate the indications for and outcome of pediatric keratoplasty. The authors retrospectively studied 164 grafts in 131 eyes of 108 children younger than 12 years of age, with an average follow-up of 45 months. This series includes 12 penetrating keratoplasties in eight eyes of six children with congenital glaucoma. The graft survival of the congenital glaucoma group was not separately analyzed, but the 12 months survival rate was 80% for eyes with congenital opaciﬁcation compared with 76% for those with acquired non-traumatic disease. Frueh and Brown10 studied 58 eyes of infants and children with congenital corneal opacities who were treated with penetrating keratoplasty. Only two eyes in this series had congenital glaucoma. The probability of maintaining a clear graft was 75% at one year and 58% at two years for the entire group, and 23 eyes had to be regrafted between 2 weeks and 110 months postoperatively. A case report by Zacharia et al11 described a clear graft at 15 months of age after simultaneous treatment with penetrating keratoplasty and valved glaucoma drainage implant to treat congenital glaucoma with severe corneal scarring. The authors suggested that combined glaucoma and corneal treatment may improve long-term graft survival. The success of penetrating keratoplasty in children with various corneal abnormalities was reported by Aasuri and coworkers.12 Clear grafts were achieved in 30 (64%) of 47 eyes with congenital opacities, with average follow-up of 1.3 years. Most of the graft failures occurred during the ﬁrst 26 weeks after surgery. Poor graft survival was correlated with age younger than 5 years. Most grafts failed due to allograft rejection (42%), infectious keratitis (27%), or secondary glaucoma (13%). Although satisfactory anatomic outcomes were achieved, the visual outcomes were poor, suggesting the importance of the timing of surgery, amblyopia therapy, and other factors. Endothelial decompensation due to congenital glaucoma is a rare indication for penetrating keratoplasty in adults (Fig. 13.2). Toker and co-workers13 identiﬁed 13 adult and three pediatric patients who underwent penetrating keratoplasty with a previous diagnosis of congenital glaucoma from a total of 3663 records of corneal transplantations. At the end of follow-up, 75% of patients with a history of congenital glaucoma had clear grafts, although 45% required regrafting. The ﬁnal postoperative visual acuity was improved in 70% of eyes. Similarly, Ramchandani and co-workers14 identiﬁed nine eyes in adults with a history of congenital glaucoma, treated with glaucoma surgery earlier in life. The age range of the patients was from 27 to 71 years at the time of surgery, with average follow-up of 28 months. Two patients (22%)

References

Figure 13.2 An adult patient with a history of congenital glaucoma and cataract. He developed increasing corneal edema later in life, due to endothelial decompensation, which required treatment with penetrating keratoplasty. He subsequently developed elevated intraocular pressure, treated with glaucoma drainage implant.

developed graft failure at 15 and 41 months postoperatively due to elevated intraocular pressure after penetrating keratoplasty. Final visual acuity was improved in ﬁve patients, the same in three patients, and worse in one patient. In aniridia patients, corneal opaciﬁcation may be progressive, with an onset later in life. Pannus formation and aniridic keratopathy responds poorly to penetrating keratoplasty alone. Keratolimbal allograft (limbal stem cell transplantation) may stabilize the ocular surface and increase corneal transplant graft survival.15 Surgical treatment of elevated intraocular pressure may be required before or after keratoplasty (Fig. 13.3).

Timing of glaucoma surgery In general, the intraocular pressure is stabilized in the normal range prior to penetrating keratoplasty. Because of the corneal opacity, initial surgical treatment is most commonly trabeculotomy rather than goniotomy. When primary surgery fails, other glaucoma treatments usually are performed prior to penetrating keratoplasty. However, combined penetrating keratoplasty and trabeculectomy with mitomycin C have been performed at the same setting.16 Penetrating keratoplasty has also been performed with the Ahmed Glaucoma Valve as a combined procedure.17

Conclusion It has not been clearly established whether corneal transplantation is indicated in the pediatric patient with a corneal opacity due to congenital glaucoma, especially in patients with unilateral corneal opacities. The results from clinical case series reported in the literature have varied widely, although anatomic success may be improving. It does appear, however, that the prognosis is guarded for penetrating keratoplasty in this group of patients while there is a possibility of improvement of the vision in some patients. The optimal timing for surgery is not known. Although the prognosis is variable and uncertain, patients with bilateral corneal opacities are candidates for penetrating keratoplasty.

A

B Figure 13.3 An adult aniridia patient with aniridic keratopathy and pannus formation (A). The appearance after keratolimbal allograft (limbal stem cell transplant) and penetrating keratoplasty (B) with a clear graft. The eye is aphakic and has been treated with glaucoma drainage implant for elevated intraocular pressure.

References 1. Waring GO 3rd, Laibson PR. Keratoplasty in infants and children. Trans Am Acad Ophthalmol Otolaryngol 1977; 83:283–296. 2. Schanzlin DJ, Goldberg DB, Brown SI. Transplantation of congenitally opaque corneas. Ophthalmology 1980; 87:1253–1264. 3. Stulting RD, Sumers KD, Cavanagh HD, et al. Penetrating keratoplasty in children. Ophthalmology 1984; 91:1222–1230. 4. Frucht-Pery J, Feldman ST, Brown SI. Transplantation of congenitally opaque corneas from eyes with exaggerated buphthalmos. Am J Ophthalmol 1989; 107:655–658. 5. Huang SCM, Soong KH, Brenz RM, et al. Problems associated with penetrating keratoplasty for corneal edema in congenital glaucoma. Ophthalmic Surg 1989; 20:399–402. 6. Cowden JW. Penetrating keratoplasty in infants and children. Ophthalmology 1990; 97:324–329. 7. Erlich CM, Rootman DS, Morin JD. Corneal transplantation in infants, children and young adults: experience of the Toronto Hospital for Sick Children, 1979–1988. Can J Ophthalmol 1991; 26:206–210. 8. Ariyasu RG, Silverman J, Irvine JA. Penetrating keratoplasty in infants with congenital glaucoma. Cornea 1994; 13:521–526. 9. Dana MR, Moyes AL, Gomes JAP, et al. The indications for and outcome in pediatric keratoplasty: a multicenter study. Ophthalmology 1995; 102:1129–1138. 10. Frueh BE, Brown SI. Transplantation of congenitally opaque corneas. Br J Ophthalmol 1997; 81:1064–1069. 11. Zacharia PT, Harrison DA, Wheeler DT. Penetrating keratoplasty with a valved glaucoma drainage implant for congenital glaucoma and corneal scarring secondary to hydrops. Ophthalmic Surg Lasers 1998; 29:318–322. 12. Aasuri MK, Garg P, Gokhle N, Gupta S. Penetrating keratoplasty in children. Cornea 2000; 19:140–144.

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Penetrating keratoplasty 13. Toker E, Seitz B, Langenbucher A, Dietrich T, Naumann GO. Penetrating keratoplasty for endothelial decompensation in eyes with buphthalmos. Cornea 2003; 22:198–204. 14. Ramchandani M, Mohammed S, Mirza S, McDonnell PJ. Penetrating keratoplasty in adults with congenital glaucomas. Eye 2004; 18:703–708. 15. Holland EJ, Djalilian AR, Schwartz GS. Management of aniridic keratopathy with keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmology 2003; 110:125–130.

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16. Figueiredo RS, Araujo SV, Cohen EJ, et al. Management of coexisting corneal disease and glaucoma by combined penetrating keratoplasty and trabeculectomy with mitomycin C. Ophthalmic Surg Lasers 1996; 27:903–909. 17. Zacharia PT, Harrison DA, Wheeler DT. Penetrating keratoplasty with a valved glaucoma drainage implant for congenital glaucoma and corneal scarring secondary to hydrops. Ophthalmic Surg Lasers 1998; 29:318–322.

Chapter 14 Glaucomas in aphakia and pseudophakia after congenital cataract surgery Introduction Ocular hypertension versus glaucoma Glaucoma after congenital cataract surgery Mean time interval at onset of glaucoma following surgery Causes of delay in diagnosis Mechanism of intraocular pressure elevation and risk factors Diagnostic clues and evaluation Treatment Conclusions

Introduction Postoperative complications occur more commonly after congenital or infantile cataract surgery compared with adult cataract surgery, and many of these complications do not develop until years after surgery.1 Little has been written about pediatric glaucoma in aphakia and pseudophakia, a recognized complication of congenital cataract surgery.2 Despite improved surgical technique utilizing vitreous cutting instrumentation for lens removal and vitreous management, the incidence of glaucoma following successful cataract removal remains high.3,4 Transient or permanent intraocular pressure elevation occurs in aphakic and pseudophakic eyes as a result of one of several mechanisms, or it can be due to a combination of several causative factors. Hence, the use of the term ‘aphakic glaucoma’ is generally discouraged because it implies that the state of aphakia as such is the only cause of glaucoma, which is not observed in clinical practice. This group of glaucomas may be described as ‘glaucomas associated with aphakia and pseudophakia’ or ‘the glaucomas in aphakia and pseudophakia,’ which conveys the notion that multiple mechanisms contribute to the development of elevation of the intraocular pressure after congenital cataract surgery (Fig. 14.1).

glaucoma. Patients who have increased intraocular pressure without apparent disc damage must be examined for disc damage and cupping over time, without the beneﬁt of visual ﬁeld testing. Egbert and coworkers5 conducted a prospective glaucoma evaluation to discover the prevalence of glaucoma and ocular hypertension in a group of pediatric subjects who underwent an automated lensectomy and anterior vitrectomy for congenital or pediatric cataracts during a nine-year period. The diagnosis of glaucoma required the intraocular pressure to be greater than 21 mmHg and the optic nerve head to have a cup-to-disc ratio greater than 0.5 or an asymmetry between optic nerve heads greater than or equal to 0.2. A diagnosis of ocular hypertension required the intraocular pressure to be greater than 21 mmHg with an absence of optic nerve abnormalities. In this study, the prevalence of glaucoma and ocular hypertension was 9.7% and 33%, respectively.5 Retrospective studies reporting the occurrence of glaucoma after surgery for congenital or pediatric cataract are limited by a short or undeﬁned postoperative and follow-up periods. Most of these studies have not consistently stated the criteria

Ocular hypertension versus glaucoma The difference between ocular hypertension and glaucoma is poorly understood in patients with aphakia and pseudophakia following surgery for congenital or infantile cataract. Children may not be able to perform visual ﬁeld testing, which may preclude the use of this important diagnostic criteria for

Figure 14.1 Elevated intraocular pressure associated with aphakia. This infant had Lowe’s syndrome (oculocerebrorenal syndrome). A contact lens has been placed to correct the large refractive error. 93

Glaucomas in aphakia and pseudophakia for glaucoma, or deﬁne glaucoma as an intraocular pressure of 21 mmHg or greater on more than one occasion. Few authors have differentiated ocular hypertension and glaucoma.5–7 The importance of carefully deﬁning the criteria for glaucoma is shown by the large increase in the prevalence of glaucoma in the study by Egbert and coworkers if they had deﬁned glaucoma as intraocular pressure of 26 mmHg or greater.5 Glaucoma would have been diagnosed in 10 additional subjects, thus increasing the prevalence of glaucoma to 26% of their patient population, instead of 6 (9.7%) of 62 subjects found to have glaucoma deﬁned as elevated intraocular pressure with glaucomatous optic nerve damage.

Table 14.2 Glaucoma after congenital cataract surgery, using automated vitrectomy and lensectomy Author

Year

Chrousos et al11

1984

6.1%

5.5

Keech et al10

1989

11.0%

3.6

Simon et al3

1991

24.0%

6.8

Robb and Petersen

1992

15.0%

Not stated

Parks et al9

1993

14.9%

5.3

Mills and Robb13

1994

15.8%

7.4

Egbert et al5

1995

9.7%

12

Miyahara et al

Glaucoma after congenital cataract surgery Glaucoma is a well-recognized consequence of congenital cataract surgery. In a review of early literature on pediatric aphakia performed between 1943 and 1975, Francois8 found an average prevalence of glaucoma of 5.5%, with some authors reporting a prevalence up to 13–14% (Table 14.1). It was noted that glaucoma may not be recognized until years after cataract removal. These reports were prior to modern microsurgical techniques, including automated lensectomy and vitrectomy. During the 1970s, microscopically controlled, automated lensectomy and vitrectomy gradually replaced one and twostaged needling as a method of pediatric cataract extraction. Lensectomy and vitrectomy remain the most commonly used technique. It was hoped that by removing lens and capsular remnants more effectively, this surgical approach would minimize postoperative inflammation and pupillary block, and would decrease the incidence of glaucoma. A study reporting the initial experience with this technique was encouraging, with no cases of glaucoma reported.9 In

Table 14.1 Secondary glaucoma after congenital cataract surgery, prior to automated vitrectomy and lensectomy Authors

Year

Falls

1943

% secondary glaucoma 8.1

Owens and Hughes

1948

2.2

Bagley

1949

2.3

Guillaumat and Girard

1954

0

Bouzas

1955

0

Leinfelder

1963

13.0

Ryan et al

1965

6.0

Kaufer

1966

2.4

Fattouh

1966

3.0

Dagasan

1966

0.9

Guillaumat et al

1966

13.0

Lersche

1968

6.1

Hammami et al

1972

14.0

Francois

1979

5.0

Adapted from Francois J. Late results of congenital cataract surgery. Ophthalmology 1979; 86:1586–1589. 94

Chen et al52

4

Proportion with glaucoma

Mean follow-up (years)

Not stated

2002

26%

9.7

2004

1 year = 37.1% 6 years = 75.9% 33 years = 100%

8.6

a longer follow-up study, Keech and associates10 found an 11% prevalence of glaucoma after lensectomy and vitrectomy. Subsequent studies reported prevalence of glaucoma ranging from 6% to 26% (Table 14.2).3–5,9–13 The reported incidence varies with the duration of follow-up after cataract surgery. A longer follow-up period has been associated with a higher prevalence of glaucoma.52 In a study by Simon and coworkers,3 with glaucoma deﬁned as intraocular pressure of 26 mmHg or greater, glaucoma was diagnosed in eight (24%) eyes of seven (27%) children. Visual ﬁeld and optic disc analysis in their patient population was difﬁcult. The intraocular pressure ranged from 26 to 50 mmHg (average 34 mmHg) in patients with glaucoma. Glaucoma was found more commonly among children followed for more than 60 months and was diagnosed up to 105 months after surgery.3 Of the 17 eyes that were followed for at least 5 years after surgery, 7 (41%) had glaucoma. The authors commented that the relatively high proportion of glaucoma in their patients may reflect, in addition to their longer period of follow-up, the directed glaucoma examination they receive. They also stated that more of their patients may be diagnosed with glaucoma in the future. Mills and Robb13 followed 125 eyes of 82 patients who underwent cataract surgery before the age of 10 years. Glaucoma developed in 13 (15.8%) of them from 5 months to 13.1 years after surgery. The authors projected a 30% prevalence of glaucoma at 13 years after cataract extraction. Asrani and Wilensky2 found glaucoma in 42 eyes (65.6%) after 10 years of age, with an average interval of 12.2 years between cataract surgery and the diagnosis of glaucoma.

Mean time interval at onset of glaucoma following surgery Glaucoma may occur in either an acute or chronic time course. Acute glaucoma may be due to angle closure and usually presents in the early postoperative period. Lens remnants or vitreous block may prevent aqueous flow through the pupil, inducing iris bombe. In the study reported by Vajpayee and

Mechanism of intraocular pressure elevation and risk factors coworkers,14 the duration between intraocular lens implantation and initial manifestations of pseudophakic pupillaryblock glaucoma varied between 12 and 16 days (mean ± standard deviation, 14 ± 2 days). Current surgical approaches more completely remove the lens and anterior vitreous, making this complication rare. Chronic angle-closure glaucoma may manifest months to years after congenital cataract surgery. Unlike angle-closure glaucoma, which usually develops soon after surgery, open-angle glaucoma is usually not diagnosed until years later. Simon and coworkers3 reported a mean interval of 6.8 years from the time of cataract surgery until glaucoma was diagnosed, while Phelps and Arafat6 reported intervals ranging from two to 45 years. Parks et al9 reported a mean onset of glaucoma of 5.3 years following congenital cataract surgery. Mills and Robb noted an average time at onset of 7.4 years for the nine patients with open-angle glaucoma in their study.13 Walton analyzed the number of patients who developed glaucoma after selected intervals following lensectomy.15 Forty of the 65 patients were not found to have glaucoma until two or more years after their lensectomy, while 24 of the 65 patients were found to have glaucoma four or more years after lensectomy. Johnson and Keech16 found that glaucoma developed in approximately one-third of their glaucoma patients within a few months following cataract surgery; while glaucoma developed in the remaining two-thirds several years after surgery. The mean time of onset of glaucoma following surgery in their study was 64.6 months in the persistent hyperplastic primary vitreous cataract group and 47.5 months in the infantile cataract group, which was not a signiﬁcant difference. The onset of glaucoma may occur several decades following congenital cataract surgery. Barnhorst and coworkers17 have observed an unusual case of lens-induced glaucoma that occurred 65 years after congenital cataract extraction. The intraocular specimen exhibited lens material, epithelial cells, and macrophages. It may have taken years for the residual lens material to denature and break into small pieces, which resulted in phacolytic and lens-particle glaucoma. This patient appeared to develop lens-induced glaucoma 65 years after congenital cataract surgery. Chrousos and associates11 found glaucoma in 24 (6.1%) eyes after a variety of surgical techniques. Eighteen cases became apparent after a 3-year follow-up period and 12 became apparent after a 6-year follow-up period. Their ﬁnding of no glaucoma after lensectomy and vitrectomy was based on an average 2-year follow-up period. Other studies have shown that glaucoma may continue to develop in aphakic children many years after surgery.3,10 Asrani and Wilensky2 reported results of their retrospective review of patients treated for glaucoma that developed after congenital cataract surgery. In their study, 42 eyes (65.6%) were diagnosed with glaucoma after 10 years of age, and the average interval between the cataract surgery and the diagnosis of glaucoma was 12.2 years. They compared their study with that of Simon and co-workers, who reported a 24% prevalence of glaucoma with a mean follow-up of 6.8 years. Since the average interval between cataract surgery and

diagnosis of glaucoma was 12.2 years, Asrani and Wilensky2 believe studies with shorter follow-up in the literature underestimate the incidence of this complication. However, in their group, a majority of the eyes (n = 37, 57.8%) were found to have glaucoma after an interval of 5 years. In addition, 17 eyes (26.6%) developed glaucoma within 5 years of cataract surgery, and six eyes were found to have glaucoma within 1 year of the cataract surgery. The prevalence of glaucoma after congenital cataract surgery is high with long-term follow-up. Chen et al52 retrospectively studied 170 eyes of 117 patients with mean ± SD 8.6 ± 7.6 years follow-up. The prevalence of glaucoma after lensectomy was 37.1% at 1 year, 75.9% by 6 years, and 100% by 33 years. Glaucoma can occur at any time after congenital cataract surgery; therefore, pediatric aphakic and pseudophakic patients should be routinely monitored for glaucoma throughout their lives.

Causes of delay in diagnosis Early diagnosis of glaucoma following congenital cataract surgery may be difﬁcult for a number of reasons. The ability to obtain intraocular pressure measurements, visual ﬁeld assessment, and careful biomicroscopic examination of the optic nerve head is often difﬁcult or impossible in these young patients. Furthermore, signs of congenital glaucoma such as epiphora, blepharospasm, photophobia, increasing corneal diameter, Haab’s stria, and corneal clouding may not be seen with pediatric glaucoma following congenital cataract surgery. Usually patients with glaucoma are without symptoms despite increased intraocular pressure. Unless the examining ophthalmologist speciﬁcally is looking for glaucoma, the diagnosis is easily missed. As a result, many children may have elevated intraocular pressures for months or years before they are ﬁrst detected. Frank signs and symptoms, such as redness and pain in the eye, are rare, especially because most of the glaucoma is the open-angle type. The presence of a clear cornea and the lack of ocular congestion gives the ophthalmologist a false sense of security. Also, symptoms such as loss of vision, especially in the unilateral cases, may never manifest or may appear very late in children, and thus the diagnosis of glaucoma may be missed. The existing loss of visual acuity accountable by amblyopia and nystagmus makes it difﬁcult for the ophthalmologist to assess the vision accurately in these children, and early detection of loss of vision caused by glaucoma is problematic. Glaucoma may threaten the vision of aphakic and pseudophakic eyes many years after congenital cataract surgery. A directed glaucoma evaluation that includes sedation or examination under anesthesia, if required, should be performed in the suggested follow-up schedule.2

Mechanism of intraocular pressure elevation and risk factors Glaucoma is one of the most common complications of congenital cataract surgery. Both open-angle and angleclosure glaucoma may develop. 95

Glaucomas in aphakia and pseudophakia

Angle-closure glaucoma In the era when needling was the treatment of choice for congenital cataract, angle-closure glaucoma occurred most commonly in the immediate postoperative period because of swelling of lens material causing pupillary block. This problem was reduced when Scheie popularized the aspiration technique. Pupillary block is also caused by a ﬁbrin membrane extending across the pupil. Less commonly, pupillary block glaucoma may develop secondary to vitreous prolapsing into the anterior chamber. In 1968, while delivering the 24th Edward Jackson Memorial Lecture, Chandler commented that ‘the principal cause of the loss of an eye after congenital cataract surgery is pupillary block leading to peripheral anterior synechia and intractable glaucoma.’18 The incidence of serious postoperative complications including glaucoma following congenital cataract surgery has undoubtedly diminished during the last few decades. Walton19 describes four types of glaucoma following congenital cataract surgery, including pupillary block glaucoma, lens material blockage of the trabecular meshwork, phacolytic glaucoma, and chronic open-angle glaucoma following absorption of lens material. Uveitis also has been reported as a cause of aphakic glaucoma. Modern surgical techniques, including the operating microscope and newer microsurgical instrumentation, have probably all but eliminated the ﬁrst three causes. Walton’s recent study15 conﬁrms the infrequent occurrence (5 of 80 glaucoma eyes, 7%) of pupillary block glaucoma after congenital cataract surgery and supports the belief that contemporary pediatric aphakic glaucoma is most often an open-angle glaucoma. In 1979, Francois8 reviewed the world literature along with his own experience on complications associated with cataract surgery in children. He enumerated the causes of angle-closure glaucoma after congenital cataract surgery as shown in Table 14.3. Vajpayee and co-workers14 reported development of pupillary block glaucoma in children after primary intraocular lens implantation in the posterior chamber secondary to iridopseudophakic synechiae. The exact pathogenesis of pupillary-block glaucoma with posterior chamber lenses is not clear and may be related to a number of other factors, including alteration of angle anatomy, forward movement of the vitreous caused by zonular or capsular disruption, pre-existing angle-closure glaucoma, and synechia formation between the lens and the iris or anterior capsule. Post-operative mydriasis, topical corticosteroids and a

Table 14.3 Causes of angle-closure glaucoma after congenital cataract surgery 1. Uveitis with seclusion or occlusion of the pupil and peripheral anterior synechiae 2. Pupillary block with inflammatory membrane 3. Delayed restoration of the anterior chamber after cataract extraction 4. Vitreous in the anterior chamber or loss of vitreous 5. Epithelial ingrowth in the anterior chamber after cataract extraction 6. Hyphema, intraocular hemorrhage 7. Prolapse of the iris 8. Associated with intraocular lens Adapted from Francois J. Late results of congenital cataract surgery. Ophthalmology 1979; 86:1586–1589.

peripheral iridectomy are all helpful in reducing the incidence of pupillary block glaucoma in children following congenital cataract surgery. Less commonly, chronic angle-closure glaucoma may develop in infantile eyes after cataract surgery. Chronic angleclosure glaucoma has been noted to occur less frequently after a lensectomy than after lens aspiration, presumably because the lens cortex is more completely removed. On the basis of clinical history and gonioscopic ﬁndings, Walton15 reported pupillary-block glaucoma in three eyes of three children after bilateral lens surgery and in two eyes after unilateral lensectomy. The majority of the children (60 of the 65 children) developed open-angle secondary aphakic glaucoma, rather than angle-closure.

Open-angle glaucoma According to recent literature, the most common type of glaucoma after congenital cataract surgery is open-angle glaucoma (Fig. 14.2). While Chandler and Grant stressed that pupillary block is the usual mechanism, they mentioned ‘quite exceptional cases’ in which numerous operations for congenital cataract were followed by open-angle glaucoma. Phelps and Arafat6 documented a series of patients with open-angle secondary glaucoma following congenital cataract surgery, and subsequently similar observations were reported by others. Phelps and Arafat6 reported 18 patients who had undergone operations for congenital cataracts in the past and were Figure 14.2 Open-angle glaucoma associated with aphakia (A). The eye has microcornea and colobomatous macrophthalmia, and esotropia. Gonioscopy shows an open anterior chamber angle (B).

B A

96

Mechanism of intraocular pressure elevation and risk factors discovered to have high intraocular pressures. The age at which elevated intraocular pressure elevations was detected ranged from 6 to 56 years, and the interval between the cataract surgery and the diagnosis of glaucoma ranged from 2 to 45 years. The level of intraocular pressure when elevation was ﬁrst detected ranged from 22 to 42 mmHg. Glaucomatous optic nerve damage was deﬁnitely present in six patients, probably present in six more, and questionable in six others. The anterior chamber angles of these patients were open. In 1983, Pressman and Crouch20 reported three cases of pediatric open-angle aphakic glaucoma. These patients had congenital cataracts extracted by the extracapsular techniques of phacofragmentation or irrigation and aspiration. Each required a secondary membranectomy and had development of glaucoma 6 to 25 months after cataract extraction. Chronic glaucoma was found in 6.1% of the eyes as reported by Chrousos and co-workers.11 Although the majority of the eyes developing glaucoma manifested the complication in 6 or more years after the cataract surgery, two cases manifested glaucoma within the ﬁrst postoperative year. One-third of the eyes developing glaucoma had a pre-existing ocular abnormality other than cataract. Therefore, possibly some of the glaucomas were destined to become manifest later in spite of cataract surgery. Secondary membrane surgery was performed in 62% of the eyes in which the aspiration procedure left the posterior capsule intact. The secondary membrane surgery itself appeared to increase the risk for development of glaucoma. Keech and associates10 found an 11% (12 eyes) incidence of glaucoma after surgery for congenital and infantile cataracts. Glaucoma associated with open angles occurred in one eye of the aspiration group and three eyes of the lensectomy and vitrectomy group. Four patients (six eyes) had anomalies of the anterior chamber angle similar to congenital glaucoma. Each eye had a flat iris plane with no angle recess and a poorly deﬁned scleral spur and ciliary body. Prominent iris processes and peripheral iris hypoplasia were present in some cases. According to the authors, anterior chamber angle abnormalities unrelated to cataract surgery may have predisposed to the development of postoperative glaucoma. Parks and colleagues9 found that aphakic glaucoma of the open-angle-type developed in 26 eyes (14.9%) of 18 patients (15.3%) treated with cataract surgery. Angle-closure glaucoma did not develop in any of the patients in this report. Simon and coworkers3 noted that glaucoma after pediatric (below the age of 11 years) lensectomy and vitrectomy is typically of the open-angle-type and asymptomatic. They speculated that a substance in the vitreous humor diffuses forward and damages the trabecular meshwork following infantile cataract surgery. There are few reports in the literature documenting that patients with bilateral cataracts who have unilateral aphakia do not usually have bilateral glaucoma, and bilateral aphakia patients do not usually have unilateral glaucoma. Munoz and associates21 reported an infant with familial cataracts in whom bilateral open-angle glaucoma developed shortly after pars plicata lensectomy with anterior vitrectomy. Simon et al3

found that of the seven patients who developed open-angle glaucoma after pediatric lensectomy and vitrectomy, one patient with bilateral asymmetric cataract developed glaucoma in the operated eye but not in the unoperated eye with its partial cataract. This supports the concept that cataract surgery is in some way responsible for the onset of the glaucoma in certain predisposed children with congenital cataracts. Microcornea has been associated with glaucoma in aphakia and pseudophakia after congenital cataract surgery (Fig. 14.3). In a study by Robb and Petersen,12 late onset of open-angle glaucoma developed in 8 of the 29 patients with extensive lens opacities and early visual impairment. In patients with less severe cataracts and visual impairment, surgery for cataract was performed after three years of age, but no patient developed delayed open-angle glaucoma in this group. Similar observations were made by Mills and Robb,13 who identiﬁed an increased relative risk of developing postoperative glaucoma in eyes with microcornea, congenital rubella syndrome, and poor pupillary dilatation with 1% cyclopentolate. Parks and colleagues9 stated that aphakic glaucoma with open angle is related to two types of cataracts: nuclear and persistent hyperplasia of the primary vitreous, both of which are associated with microcornea. Forty-ﬁve of 48 patients (94%) in the study reported by Wallace and Plager22 had microcornea associated with aphakic glaucoma. In this series, seven of the eight cases of unilateral aphakia and glaucoma had smaller corneal diameters in the aphakic eye compared with the normal eye. This is similar to the report by Parks and coworkers9 that 23 of 26 patients (88%) with aphakic glaucoma had microcornea. According to the experience of Wallace and Plager,22 the majority of cases of aphakic glaucoma in children have open angles. They suspected that microcornea is indicative of an abnormal anterior segment and angle development that results in a deﬁcient angle ﬁlter mechanism, and that this altered ﬁltering mechanism is the major factor responsible for the development of glaucoma in these patients. The cause of the open-angle glaucoma may remain uncertain in most of the patients who develop open-angle glaucoma after cataract surgery. Both mechanical and chemical theories have been proposed.23 One possibility is that release of tension on the zonules after removal of the lens may reduce traction on the trabecular meshwork, potentially decreasing the trabecular spaces and reducing outflow facility. Another possibility is the influence of lens particles

Figure 14.3 Microcornea and aphakia. The patient is now an adult and has developed elevated intraocular pressure. 97

Glaucomas in aphakia and pseudophakia or proteins, inflammatory cells, and vitreous-derived factors on the trabecular meshwork. Also, the possibility of a steroidinduced glaucoma is high, because steroids are used for a longer period after cataract surgery in children who usually show increased inflammation, even with the newer techniques of cataract surgery.

Risk factors Development of glaucoma in aphakia and pseudophakia after congenital cataract surgery is multifactorial. Its occurrence has been associated with risk factors, including age at surgery, pre-existing ocular abnormalities, type of cataract, and the effect of lens particles, lens proteins, inflammatory cells, and retained lens material. In addition, microcornea, secondary surgery, chronic postoperative inflammation, the type of lensectomy procedure or instrumentation, pupillary block, and the duration of postoperative observation have been found to influence the likelihood of glaucoma after pediatric cataract surgery. Rabiah24 identiﬁed several strong predictors of glaucoma after pediatric cataract surgery, including surgery at ≤ 9 months of age, secondary membrane surgery, microcornea, and primary posterior capsulotomy with anterior vitrectomy. In this study, chronic glaucoma was common after cataract surgery performed at or before, but not after, a threshold age in childhood (approximately 9 months). Glaucoma developed in 37% of eyes after cataract surgery at ≤ 9 months of age, and 6% in eyes undergoing cataract surgery after 9 months of age during an average 9 years follow-up. Survival analysis predicted higher rates of glaucoma with longer follow-up (Fig. 14.4).

Diagnostic clues and evaluation Glaucoma evaluation in aphakia and pseudophakia following congenital cataract surgery should include assessment

Percent with glaucoma

100 Age 9 months at surgery Age > 9 months at surgery

80 60 40 20 0

0

5 10 Years after surgery

15

Figure 14.4 Survival curve analysis for development of glaucoma after pediatric cataract surgery. The data was estimated from multivariable Cox proportional hazards model with adjustment for intrasubject correlation. In this study, age at time of cataract surgery was a risk factor for the development of glaucoma, with a higher risk in children who underwent cataract surgery up to 9 months of age. Modified with permission from Rabiah PK. Frequency and predictors of glaucoma after pediatric cataract surgery. Am J Ophthalmol 2004; 137:30–37. 98

of corneal diameter, slit-lamp evaluation, applanation tonometry, and estimation of the glaucomatous optic nerve damage. Visual ﬁeld measurements can be performed with the Goldmann perimeter or with automated perimetry (Humphrey, Octopus, and others), if the child is old enough to co-operate. The diagnosis of glaucoma may be difﬁcult to establish in children after congenital cataract surgery since they often lack the classic signs of congenital glaucoma, such as buphthalmos, epiphora, and blepharospasm. Moreover, the intraocular pressure may be difﬁcult to measure with the child awake, and the view of the optic disc may be compromised by lens remnants, miosis, and nystagmus. Also, visual ﬁelds usually cannot be accurately assessed until later in childhood. When an adequate examination cannot be obtained while a child is awake, an examination should be performed under sedation or general anesthesia, especially if there is a high index of suspicion of glaucoma. An ideal evaluation should include measurement of the corneal diameter, intraocular pressure, cycloplegic refraction and an optic nerve head evaluation. Ancillary testing should include measurement of axial length by A-scan ultrasonography and optic nerve head photographs. Measurements of corneal diameter is important, not only to identify buphthalmos, but also to identify microcornea, which has been associated with pediatric aphakic glaucoma. Wallace and Plager22 found that 45 of the 48 (94%) eyes in their series had microcornea when compared with the normal corneal diameter of their age. They concluded that the clinician should be aware that the children with a small corneal diameter at the time of surgery are at risk for glaucoma. If the corneal diameter is noted to be smaller than normal for the child’s age or, in the cases of unilateral cataract, smaller than the phakic eye, the child should be followed closely throughout childhood and beyond for signs of glaucoma. Egbert and Kushner25 presented four patients of juvenile aphakic glaucoma in whom an excessive loss of hyperopia was the initial clinical sign that alerted them to the diagnosis of glaucoma. The authors believe that this is an important sign in patients who are unable to cooperate with intraocular pressure measurements and visual ﬁeld or meticulous optic nerve head examinations. They believe aphakic patients exhibiting a marked loss of hyperopia should be considered glaucoma suspects. Walton15 mentioned that in absence of regular tonometry, recognition of corneal clouding, ocular enlargement, and contact lens intolerance aided in the diagnosis of glaucoma in his series of 65 children who had glaucoma after congenital cataract surgery. The appearance of anterior chamber angle is very important in disclosing the mechanism of glaucoma in the aphakic or pseudophakic eye following congenital cataract surgery. Walton15 performed gonioscopic evaluation with Koeppe gonioscopy, a Barkan hand-held microscope with 6 × magniﬁcation, and a hand-held light. Abnormalities were found in the angles of 76 of the 80 glaucoma eyes. The angles were open in 79 of 80 eyes; however, 5 eyes with a history of treated pupillary block glaucoma showed variable degrees of peripheral anterior synechiae. In 1 of these 5 eyes, very little

Treatment open angle was present. In the 79 eyes with open angles, the most consistent defect was a circumferential repositioning of the iris insertion anteriorly at the level of the posterior or mid trabecular meshwork, with resultant loss of view of the ciliary body band and scleral spur. Scattered pigment deposits were frequent; less frequent were white crystalline deposits suggestive of residual lens material caught in the meshwork. The frequency of follow-up examinations after pediatric cataract surgery varies depending upon individual patient factors. In one recommendation for follow-up examinations after infantile cataract surgery, screening examinations for glaucoma were suggested for every three months during the ﬁrst postoperative year, twice yearly until the 10th year, and annually thereafter.2

Treatment Medical Initial medical treatment is usually tried in children with aphakia or pseudophakia and glaucoma, because the surgical options in these eyes are less successful and are associated with greater morbidity than in phakic eyes. Medical therapy with beta-blockers, carbonic anhydrase inhibitors, and prostaglandin-related drugs may be used, as described in Chapter 9. Pilocarpine (1 or 2%), which has a better sideeffect proﬁle in aphakic or pseudophakic patients compared with phakic patients, may also be helpful. The risk of retinal detachment has to be borne in mind with pilocarpine. Epinephrine or propine are not useful because of the low efﬁcacy of these drugs and the risk of cystoid macular edema. Pressman and Crouch20 reported 3 cases of pediatric aphakic glaucoma initially treated with medical treatment, but long-term control of intraocular pressure was not achieved. In the series reported by Asrani and Wilensky,2 medications alone successfully controlled the intraocular pressure in 21 (63.6%) of 33 eyes. In the series reported by Simon and colleagues,3 six of eight eyes were controlled medically (below 21 mmHg) with a combination of miotics and beta-blockers. Unlike primary congenital glaucoma, which responds poorly to medical therapy, it appears that at least some patients with glaucoma associated with aphakia or pseudophakia may achieve long-term control of intraocular pressure with medical therapy alone. In some types of glaucoma in aphakia and pseudophakia, there may be an element of inflammation, which warrants anti-inflammatory treatments together with the antiglaucoma treatment. Miotics and prostaglandin analogues should be avoided in such cases.

Laser treatment The argon or diode lasers are usually not effective in management of glaucoma associated with aphakia or pseudophakia in children. Pressman and Crouch20 performed argon laser trabeculoplasty in one case using 100 to 150 spots with 50 μm spot size and 1000–1250 mW with a duration of 0.1 second. This treatment was not effective. The Nd:YAG laser is particularly useful for iridotomy in pupillary block glaucoma in children. Vajpayee and co-

workers14 reported a series of 16 children with pseudophakic pupillary-block glaucoma that was managed with Nd:YAG laser iridotomy. After intraocular pressure was controlled initially with medications, Nd:YAG laser iridotomy was performed within two to three days in all eyes. Initial Nd:YAG iridotomy failed in all eyes, but repeat Nd:YAG iridotomy one week later was performed successfully in all eyes. Satisfactory control of intraocular pressure was achieved in 13 of 16 patients (81%) after Nd:YAG iridotomy.

Surgical treatment Surgical iridectomy With the advent of Nd:YAG laser, laser iridotomy is the procedure of choice. There are few indications for surgical iridectomy when laser facilities are available. In the series reported by Vajpayee and co-workers,14 no patient required surgical iridectomy, although all patients required repeat Nd:YAG laser procedure to relieve pseudophakic pupillaryblock glaucoma. However, if Nd:YAG iridotomy fails repeatedly, surgical iridectomy is advisable, especially in patients with severe postoperative inflammation leading to pupillary block glaucoma. However, in such a situation, the clinician should evaluate whether iridotomy alone will be sufﬁcient or a more deﬁnitive ﬁltering surgery will be required.

Filtering surgery with or without antifibrosis drugs Trabeculectomy is the most commonly performed ﬁltering surgery in aphakia and pseudophakia following infantile cataract surgery, but the success rate is variable. Barriers to success include a thick and active Tenon’s capsule with rapid wound healing response in children.26 Aphakia or pseduophakia and young age are risk factors for failure of trabeculectomy.27–29 Pressman and Crouch20 reported three children with pediatric aphakic glaucoma who showed poor results with trabeculectomy and required repeat surgery. Trabeculectomy alone was successful in three out of ﬁve eyes whereas trabeculectomy with antimetabolite was successful in controlling the intraocular pressure in six out of seven eyes as reported by Asrani and Wilensky.2 Walton15 assessed the results of surgical treatment for 42 eyes of the 65 children. Initially, goniosurgical procedures were performed, with 11 goniotomy operations for 13 eyes considered failures. Trabeculectomy with mitomycin-C was helpful for 9 of 14 eyes (64%) with pediatric aphakic glaucoma. Lichter commented that trabeculectomy with antimetabolite is probably the preferred approach in managing glaucoma in aphakia and pseudophakia following congenital and infantile cataract surgery. Antiﬁbrosis drugs are known to inhibit ﬁbroblast proliferation and have been found to improve the success rate of ﬁltering surgery in adults as well as in children.30 MitomycinC and 5-fluorouracil (5-FU) are the most commonly used antiﬁbrotic agents in glaucoma ﬁltering surgery. Subconjunctival injection of 5-FU in children requires use of multiple 99

Glaucomas in aphakia and pseudophakia general anesthesias31 and thereby is not a suitable option in children with aphakic or pseudophakic glaucoma. Moreover, several prospective randomized studies in adults with high risk glaucoma ﬁltering surgery have shown that intraoperative mitomycin-C may be a better alternative to postoperative 5-FU because mitomycin-C has resulted in lower overall intraocular pressure, decreased dependence on postoperative antiglaucoma medications, and decreased corneal toxicity. Several reports have been recently published on the successful use of mitomycin-C in children with refractory congenital glaucoma.32–34 Reports of clinical experience with trabeculectomy with mitomycin-C in pediatric aphakic and pseudophakic glaucoma are summarized in Table 14.4.2,15,34–39 With the exception of the report by Azuara-Blanco et al,37 the success rate varied from 50% to 85%. According to Wallace et al,35 trabeculectomy with mitomycin-C is the most effective treatment in aphakic glaucoma following congenital cataract surgery. In contrast, Azuara-Blanco et al37 had a poor outcome and commented that an alternative approach to aphakic childhood glaucoma may be necessary. The optimal dose of mitomycin-C in children is yet unknown, although clinicians often use dosage of mitomycin-C ranging from 0.2 to 0.4 mg/ml for 2–3 minutes, which is safe and effective in children with aphakic and pseudophakic glaucoma based on our personal experience. However, prospective, randomized controlled clinical studies with larger number of patients and longer follow-up period are required to determine the optimal dosage and the application time of mitomycin-C, as well as the ocular and systemic factors that may predispose the eyes with refractory glaucoma to late complications. Early complications like shallow anterior chamber, corneal epitheliopathy, and hypotony with or without choroidal detachment are managed according to the standard treatments. Devastating complications, such as late infections, remain a potential danger with the use of

mitomycin-C as adjunctive therapy during trabeculectomy with refractory glaucoma in aphakia and pseudophakia following congenital cataract surgery.34–36,39 After trabeculectomy with mitomycin-C, these children require periodic examinations and the parents should be educated about the possible late complications.34

Glaucoma drainage implants Drainage implant surgery appears to be a viable option for the management of those patients that are unresponsive to medical treatment or an initial conventional glaucoma ﬁltering surgery. These drainage devices have been designed to maintain communication between the anterior chamber and the subconjunctival or sub-Tenon’s space posterior to the limbus (near the equator), in cases where there is a high risk of scarring of the ﬁltration ﬁstula. Certain implants have flowresistive valves (Ahmed and Krupin implants), whereas others are open-tube, non-valved implants (Molteno and Baerveldt implants). The long-term bleb-related complications and the potential risk of chemotherapeutic exposure are avoided with the use of drainage implants. Encouraging reports obtained with the Molteno implants in young patients have led several investigators to use other implants in children with refractory glaucomas, including children with aphakia or pseudophakia. Satisfactory success rates have been reported by several investigators.40–45 Contradictory reports have also been published, with variable success rates ranging from 33% to 60%.35,46,47 In general, the success rates of glaucoma drainage devices in refractory pediatric glaucoma are variable and also the complication rates vary. Drainage implants may be a useful alternative to trabeculectomy with mitomycin-C for aphakic patients who are contact lens dependent, and who may be at greater risk for late-onset bleb-related infection and endophthalmitis after surgery.48

Table 14.4 Reported series on trabeculectomy with mitomycin-C In pediatric aphakic and pseudophakic glaucoma Author, Year

No. eyes

Procedure

Success criteria

Walton, 199515

14

Trab + MMC

NS

64

Asrani and Wilenski, 19952

12

Trab + MMC

IOP < 22 mmHg

85

Wallace et al, 199835

13

Trab + MMC, 4 min 0.2 or 0.4 mg/ml

IOP < 26 mmHg or <21 mmHg with meds

61

Beck et al, 199836

9

Trab + MMC, 5 min 0.25 or 0.5 mg/ml

IOP < 22 mmHg with or without meds

78

Azuara-Blanco et al, 199937

8

Trab + MMC, 1–5 min, 0.4 mg/ml

IOP < 21 mmHg without meds

0

Freedman et al, 199938

4

Trab + MMC, 3–5 min, 0.4 mg/ml

IOP 4–16 mmHg with meds

50

Sidoti et al, 200039

3

Trab + MMC, 1.5–8 min, 0.5 mg/ml

IOP 5–21 mmHg with meds

67

Trab + MMC, 2–3 min, 0.4 mg/ml

IOP 6–21 mmHg without meds with meds

Mandal et al, 200334

23

Trab, trabeculectomy; MMC, mitomycin-C; NS, not specified; IOP, intraocular pressure; meds, glaucoma medications.

100

Success (%)

37 58

References

Cyclodestructive procedures Cyclophotocoagulation is usually considered for eyes with poor vision that are refractory to other treatments. Previously, cyclocryotherapy was the most commonly used method of cycloablation, but cyclophotocoagulation with the diode laser has become popular. Laser cycloablation is generally better tolerated by patients. Both cyclocryotherapy and cyclophotocoagulation have been used for treatment of pediatric aphakic and pseudophakic eyes that are refractory to other treatments.49,50 Success rates with long-term follow-up are low, and serious vision-threatening complications may occur. Repeated cyclophotocoagulation treatments may have a role as a temporizing measure, as an adjunct to surgery, or in managing select patients in whom surgery is undesirable because of a high risk of surgical complications.51

Conclusions Up to a quarter or more of pediatric patients with pseudophakia or aphakia may develop glaucoma after cataract surgery.24 The onset of glaucoma may occur years after cataract surgery, thus the proportion of affected children increases with longer follow-up. Patients may develop angleclosure glaucoma, but more commonly develop open-angle glaucoma. Life-long monitoring for glaucoma is necessary. Antiglaucoma medications may be helpful in some patients, whereas laser therapy for open-angle glaucoma is generally not effective. Patients with aphakia or pseudophakia and glaucoma that is refractory to medical therapy may be treated with trabeculectomy with mitomycin-C or glaucoma drainage implant.

References 1. Lambert SR, Drack AV. Infantile cataracts. Surv Ophthalmol 1996; 40:427–458. 2. Asrani SG, Wilensky JT. Glaucoma after congenital cataract surgery. Ophthalmology 1995; 102:863–867. 3. Simon JW, Mehta N, Simmons ST, et al. Glaucoma after pediatric lensectomy/vitrectomy. Ophthalmology 1991; 98:670–674. 4. Miyahara S, Amino K, Tanihara H. Glaucoma secondary to pars plana lensectomy for congenital cataract. Graefe’s Arch Clin Exp Ophthalmol 2002; 240:176–179. 5. Egbert JE,Wright MM, Dahlhauser KF, et al. A prospective study of ocular hypertension and glaucoma after pediatric cataract surgery. Ophthalmology 1995; 102:1098–1101. 6. Phelps CD, Arafat NI. Open-angle glaucoma following surgery for congenital cataracts. Arch Ophthalmol 1977; 95:1985–1987. 7. Bradford GM, Keech RV, Scott WE. Factors affecting visual outcome after surgery for bilateral congenital cataracts. Am J Ophthalmol 1994; 117:58–64. 8. Francois J. Late results of congenital cataract surgery. Ophthalmology 1979; 86:1586–1589. 9. Parks MM, Johnson DA, Reed GW. Long-term visual results and complications in children with aphakia. A function of cataract type. Ophthalmology 1993; 100:826–840. 10. Keech RV, Tongue AC, Scott WE. Complications after surgery for congenital and infantile cataracts. Am J Ophthalmol 1989; 108:136–141. 11. Chrousos GA, Parks MM, O’Neill JF. Incidence of chronic glaucoma, retinal detachment and secondary membrane surgery in pediatric aphakic patients. Ophthalmology 1984; 91:1238–1241. 12. Robb RM, Petersen RA. Outcome of treatment for bilateral congenital cataracts. Ophthalmic Surg 1992; 23:650–656. 13. Mills MD, Robb RM. Glaucoma following childhood cataract surgery. J Pediatr Ophthalmol Strabismus 1994; 31:355–360.

14. Vajpayee RB, Angra SK, Titiyal JS,et al. Pseudophakic pupillary-block glaucoma in children. Am J Ophthalmol 1991; 111:715–718. 15. Walton DS. Pediatric aphakic glaucoma. A study of 65 patients. Trans Am Ophthalmol Soc 1995; 93:403–413. 16. Johnson CP, Keech RV. Prevalence of glaucoma after surgery for PHPV and infantile cataracts. J Pediatr Ophthalmol Strabismus 1996; 33:14–17. 17. Barnhorst D, Meyers SM, Myers T. Lens-induced glaucoma 65 years after congenital cataract surgery. Am J Ophthalmol 1994; 118:807–808. 18. Chandler PA. Surgery of congenital cataract. Am J Ophthalmol 1968; 65:663–674. 19. Walton DS. Glaucoma secondary to operation for childhood cataract. In: Epstein DL, ed. Chandler and Grant’s glaucoma. Lea & Febiger: Philadelphia, PA; 1986:521–525. 20. Pressman SH, Crouch ER. Pediatric aphakic glaucoma. Ann Ophthalmol 1983; 15:568–573. 21. Munoz M, Parrish RK, Murray TG. Open-angle glaucoma after pars plicata lensectomy and vitrectomy for congenital cataracts. Am J Ophthalmol 1995; 119:103–104. 22. Wallace DK, Plager DA. Corneal diameter in childhood aphakic glaucoma. J Pediatr Ophthalmol Strabismus 1996; 33:230–234. 23. Asrani S, Freedman S, Hasselblad V, et al. Does primary intraocular lens implantation prevent ‘aphakic’ glaucoma in children? J AAPOS 1999; 3:33–9. 24. Rabiah PK. Frequency and predictors of glaucoma after pediatric cataract surgery. Am J Ophthalmol 2004; 137:30–37. 25. Egbert JE, Kushner BJ. Excessive loss of hyperopia. A presenting sign of juvenile aphakic glaucoma. Arch Ophthalmol 1990; 108:1257–1259. 26. Beauchamp GR, Parks MM. Filtering surgery in children: barriers to success. Ophthalmology 1979; 86:170–180. 27. Tomey KF, Traverso CE. The glaucomas in aphakia and pseudophakia. Surv Ophthalmol 1991; 36:79–112. 28. Heuer DK, Gressel MG, Parrish RK II, et al. Trabeculectomy in aphakic eyes. Ophthalmology 1984; 91:1045–1051. 29. Gressel MG, Heuer DK, Parrish RK II. Trabeculectomy in young patients. Ophthalmology 1984; 91:1242–1246. 30. Skuta GL, Parrish RK II. Wound healing in glaucoma ﬁltering surgery. Surv Ophthalmol 1987; 32:149–170. 31. Zalish M, Leiba H, Oliver M. Subconjunctival injection of 5-fluorouracil following trabeculectomy for congenital and infantile glaucoma. Ophthalmic Surg 1992; 23:203–205. 32. Mandal AK, Walton DS, John T, et al. Mitomycin C augmented trabeculectomy in refractory congenital glaucoma. Ophthalmology 1997; 104:996–1003. 33. Mandal AK, Prasad K, Naduvilath TJ. Surgical results and complications of mitomycin C-augmented trabeculectomy in refractory developmental glaucoma. Ophthalmic Surg Lasers 1999; 30:473–480. 34. Mandal AK, Bagga H, Nutheti R, Gothwal VK, Nanda AK. Trabeculectomy with or without mitomycin-C for paediatric glaucoma in aphakia and pseudophakia following congenital cataract surgery. Eye 2003; 17:53–62. 35. Wallace DK, Plager DA, Snyder SK, et al. Surgical results of secondary glaucomas in childhood. Ophthalmology 1998; 105:101–111. 36. Beck AD, Wilson WR, Lynch MG, et al. Trabeculectomy with adjunctive mitomycin-C in pediatric glaucoma. Am J Ophthalmol 1998; 126:648–657. 37. Azuara-Blanco A, Wilson RP, Spaeth GL, et al. Filtration procedures supplemented with mitomycin C in the management of childhood glaucoma. Br J Ophthalmol 1999; 83:151–156. 38. Freedman SF, McCormick K, Cox TA. Mitomycin C-augmented trabeculectomy with postoperative wound modulation in pediatric glaucoma. J AAPOS 1999; 3:117–124. 39. Sidoti PA, Belmonte SJ, Liebmann JM, et al. Trabeculectomy with mitomycin-C in the treatment of pediatric glaucomas. Ophthalmology 2000; 107:422–429. 40. Molteno ACB, Ancker E, Biljon GV. Surgical technique for advanced juvenile glaucoma. Arch Ophthalmol 1984; 102:51–57. 41. Billson F, Thomas R, Alward W. The use of two stage Molteno implants in developmental glaucoma. J Pediatr Ophthalmol Strabismus 1989; 26:3–8. 42. Munoz M, Tomey KF, Traverso C, et al. Clinical experience with the Molteno implant in advanced infantile glaucoma. J Pediatr Ophthalmol Strabismus 1991; 28:68–72. 43. Netland PA, Walton DS. Glaucoma drainage implants in pediatric patients. Ophthalmic Surg Lasers 1993; 24:723–729. 44. Hill RA, Heuer DK, Baerveldt G, et al. Molteno implantation for glaucoma in young patients. Ophthalmology 1991; 98:1042–1046. 45. Fellenbaum PS, Sidoti PA, Heuer DK, et al. Experience with the Baerveldt implant in young patients with complicated glaucomas. J Glaucoma 1995; 4:91–97. 46. Nesher R, Sherwood MB, Kass MA, Hines JL, Kolker AE. Molteno implants in children. J Glaucoma 1992; 1:228–232.

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Glaucomas in aphakia and pseudophakia 47. Coleman AL, Smyth RJ, Wilson MR, et al. Initial clinical experience with the Ahmed glaucoma valve implant in pediatric patients. Arch Ophthalmol 1997; 115:186–191. 48. Bellows AR, McColley JP. Endophthalmitis in aphakic patients with implanted ﬁltering blebs wearing contact lenses. Ophthalmology 1981; 88:839–843. 49. Bock CJ, Freedman SF, Buckley EG, Shields MB. Transcleral diode laser cyclophotocoagulation for refractory pediatric glaucomas. J Pediatr Ophthalmol Strabismus 1997; 34:235–239.

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50. Wagle NS, Freedman SF, Buckley EG, et al. Long-term outcome of cyclocryotherapy for refractory pediatric glaucoma. Ophthalmology 1998; 105:1921–1926. 51. Kirwan JF, Shah P, Khaw PT. Diode laser cyclophotocoagulation: role in the management of refractory pediatric glaucomas. Ophthalmology 2002; 109:316–323. 52. Chen TC, Walton DS, Bhatia LS. Aphakic glaucoma after congenital cataract surgery. Arch Ophthalmol 2004; 122:1819–1825.

Chapter 15 Management of residual vision in pediatric glaucoma Introduction Goals of low vision evaluation Low vision assessment Management Conclusions

Introduction Parents may develop frustration, guilt, and confusion after the birth of a visually impaired child. However, the development of a visually impaired child is similar to that of a sighted child, except that the process is slower.1 The later the onset of visual impairment due to developmental glaucoma, the more normal is the child’s development because of the acquisition of visual memory in the intervening period. According to Barraga,2 visual functioning is a learned behavior that is ‘primarily developmental.’ More visual experiences stimulate additional pathways of the brain, which leads to greater accumulation of a variety of visual images and memories. Early intervention may restore and maintain visual functioning, which allows the child to develop and function as close to normal as possible.

Goals of low vision evaluation One objective of the low vision evaluation is to determine the extent of vision and thereby provide an accurate description of the child’s ability to function. Another objective is to provide low vision devices in order to increase the child’s functioning capacity.

Low vision assessment A low vision assessment in patients with developmental glaucoma should follow a structured approach that allows accurate description of the level of visual function.

History The history should be obtained from the immediate caregiver (usually the parents) or a person who knows best about the visually impaired child. The history should include information about the development of the child, including milestones of development, prenatal, and antenatal history. In older children, the history should also include information about their use of vision, including their mobility, academic

activities, book reading, school performance, and peer group interactions. Any additional disabilities and their treatments by other professionals should also be recorded.

Visual acuity Distance acuity Because developmental glaucoma manifests itself at birth or early infancy,3 visual function should be assessed as early as possible, in order to provide the caregiver with appropriate suggestions for visual stimulation. Visual acuity measurement provides a baseline measurement from which the amount of magniﬁcation needed and other treatments can be determined. These measurements also enable the practitioner to educate the parents and teachers of the visually impaired child about the child’s visual abilities and limitations. The testing of the vision of a child with developmental glaucoma varies depending on the age of the child (Table 15.1). In infants, an estimate of visual abilities can be judged by observation of the pupillary reaction to light, head turn towards a light source, blink response to a bright light, and oculokinetic nystagmus response.4 These responses may not be obtained if the child is very photophobic.3 As the child grows older (preverbal age group), a variety of tests may be employed for vision assessment. These tests include preferential looking tests (for example, Teller acuity cards, Cardiff acuity cards), visually evoked potential, and Catford drum (Fig. 15.1). Tests for vision in preverbal children

Table 15.1 Vision testing in infants and children Infants Pupillary reaction to light Head turn toward a light source Blink response to bright light Oculokinetic nystagmus response Preverbal children Preferential looking tests Teller acuity cards, Cardiff acuity cards Visually evoked potential Catford drum Older children Light House symbol test Landold’s C, Illiterate E HOTV test Snellen charts Sheridan–Gardiner test

103

Management of residual vision

Figure 15.2 Assessment of stereopsis. Figure 15.1 Preferential looking test for vision assessment.

are available in specialized pediatric ophthalmology ofﬁces.5 In older children (3 years and older), optotypes may be used for vision assessment. Some of these include the Light House symbol test,6 Landolt’s C, Illiterate E, HOTV test, Snellen charts, and the Sheriden–Gardiner test. Near acuity In young children (preschool), tests that require the naming or matching of letters,7 numbers, or symbols should be used. In older children, their own textbooks may be used to assess near acuity. Usually the near acuity is better than the corresponding distance acuity in children. This is because of the ample accommodation in the younger age group. These children are able to read by holding the reading material close to their face.8

Refraction 9

Large refractive errors may be overlooked in children. In 220 children in an urban tertiary eye center in South India, correction of ametropia with spectacles was the most common treatment (30%) provided to children with low vision.10 Children with advanced developmental glaucoma usually have axial high myopia, resulting from elongation of the eyeball due to increased intraocular pressure.3 These children may also have irregular astigmatism due to Haab’s striae or other causes. The refraction may be difﬁcult if the children are photophobic. In such cases and in infants, refraction is best performed during examination under anesthesia. In eyes with a poor retinoscopic reflex, retinoscopy may be performed at a very close distance (‘radical retinoscopy’).11 When this procedure fails to produce a retinoscopic reflex, biometry may be helpful.12,13 When the examiner suspects astigmatic errors, keratometry may be performed. A rough estimate of the refractive error can be obtained by determining the dioptric power necessary to visualize the fundus using the direct ophthalmoscope, although this procedure does not account for astigmatic errors.14 For infants, the examiner provides the refractive correction based on the objective refraction. Accurate refractive correction is essential, in order to form a clear image on the child’s retina. In older children, subjective refraction may also be performed. The examiner should avoid the use of the phoropter, instead use appropriate pediatric trial frames or lenses that are comfortable for the child.11 104

Binocularity In about two-thirds of cases of developmental glaucoma, the disease is bilateral with one eye at a more advanced stage than the fellow eye.3 In these asymmetric cases, there is often lack of binocularity. When the child is binocular and has asymmetric acuities in the two eyes, low vision devices are provided for the better eye. The most reliable tests for binocularity are the cover test and monocular acuities.11 Stereopsis can be assessed in older children using various commercial devices (Fig. 15.2). When a child is functionally monocular, patching the weaker eye may be useful. Retinal rivalry can exist when the visual acuity in one eye is about 2/60 and 6/36 in the better eye.11

Visual fields Although young children may not be able to perform perimetry, visual ﬁeld examination should be performed whenever possible (Fig. 15.3). The visual ﬁeld examination helps to determine whether the visual loss is sufﬁcient to affect the child’s mobility and performance with the prescribed low vision devices.9 When severe peripheral ﬁeld loss is present, the child will require mobility or vision efﬁciency training. When formal visual ﬁeld testing is not possible, information about the child’s navigational abilities in familiar and unfamiliar areas may be useful.

Illumination Children with developmental glaucoma are often photophobic.3 They may prefer the indoor, less brightly illuminated

Figure 15.3 Automated perimetry to assess visual field may be performed in older children.

Management environment to outdoor play activities. Light-controlling devices, including visors, wide-brimmed hats, and sun ﬁlters,9 may be useful in brightly illuminated areas.15 In appropriate patients, glare can be assessed using Brightness Acuity Tester.16

Contrast sensitivity In adults, contrast sensitivity is affected in the early stages of glaucoma, perhaps before any clinically visible damage.17 Liou and Chiu18 have shown that contrast sensitivity losses occur in medium (6 to 12 diopters) and high myopes (>12 diopters) corrected with spectacles. High power spectacle lenses can introduce signiﬁcant aberrations, including oblique astigmatism, curvature of the ﬁeld, distortion, and chromatic aberration, which can lead to image degradation.19 The aberrations and image degradation influence higher spatial frequencies,20,21 but contact lenses can reduce these aberrations.22 Although little is known about contrast sensitivity in patients with developmental glaucoma, these children are often myopic and corrected with spectacles, which is likely associated with abnormalities of contrast sensitivity. Contrast-enhancing measures include use of bold-line notebooks and black felt-tip pens in school-age children. An infant who does not give a social smile is considered unresponsive and may receive less attention. If the contrast sensitivity is impaired, appropriate measures to improve the contrast in the child’s environment may be helpful. Contrast on the face of the mother may be improved by application of dark colored lipstick. Infants can wear brightly colored half-mittens, nail polish, or bracelets to enable them to look at their hands.23 Older children with impaired contrast sensitivity will require more magniﬁcation than would be expected by their level of visual acuity and they beneﬁt from increased illumination when performing near-range tasks such as reading.

Management The management of the visually impaired child with developmental glaucoma begins with accurate refractive correction. High refractive index material in high myopic spectacles may reduce the weight of the glasses and decrease the thickness of the lenses, which increases patient acceptance.

Devices If the child has problems with distance vision tasks (for example, chalkboard work) despite refractive correction and appropriate environmental modiﬁcations (for example, sitting near the chalkboard), telescopes are recommended (Fig. 15.4). These telescopes may be hand-held or spectaclemounted. Usually 4× is the best option in telescopes, providing a useful compromise between adequate magniﬁcation and ﬁeld of view.24 Apart from the cost, the appearance of these telescopes is a major barrier to their acceptance. In many instances, children with developmental glaucoma may not need any low vision device for near work (Fig. 15.5).

Figure 15.4 Telescope for distance vision tasks.

Figure 15.5 Near reading with spectacle correction.

If children have problems with reading ﬁne print (for example, in dictionaries and maps), low-powered hand or pocket magniﬁers (2× to 3×) may be helpful. The examiner should reassure the parents about close reading distances. A reading stand or other non-optical devices may improve comfort and reduce postural problems due to close reading distances. Reading lamps with fluorescent light may improve contrast and facilitate reading. Other non-optical devices include sun ﬁlters, photochromic lenses, hats with visors or broad brims, bold-line notebooks, and black felt-tip pens.

Training In addition to providing low vision devices, children should be trained in the use of these devices.11 The reduced ﬁeld of vision and spatial distortions associated with some of the low vision devices require children to learn new motor patterns that involve head, hand, and eye coordination. Structured training programs in the use of low vision devices should be planned and discussed with the child and parents. The training should be appropriate for the recommended devices. Telescopes for distance vision require an explanation and a demonstration of the inherent limitations of the ﬁeld of view and parallax displacement of objects. Training can be provided in a simulated classroom setting. Low vision devices should be dispensed after the child has demonstrated proﬁciency in their use. The low vision 105

Management of residual vision specialist should also provide a detailed evaluation report to the teacher so that the teacher can assist the child with the use of low vision devices in the classroom. Teachers of visually impaired children often provide a liaison between the low vision clinic, home, and school.25 Orientation and mobility training helps the visually impaired child to become independent in school and in the community. Children with extensive peripheral ﬁeld loss leading to problems in mobility may be provided with mobility training by an orientation and mobility instructor. Children with other impairments, such as hearing loss and mental retardation, should be referred to the appropriate professionals for their management.

Severe vision impairment In a study of 91 children with microphthalmos, coloboma, and microcornea, Hornby and colleagues found that conventional spectacles improved vision signiﬁcantly in about 51% of the children.24 They recommended that low vision assessment should be performed in any child who has bestcorrected visual acuity in the better eye of between 6/18 and 1/60. Low vision devices were rarely useful in cases of visual acuity less that 1/60 in the better eye. Children with severe vision impairment (visual acuity less that 1/60 in the better eye) who also have corresponding poor near acuities beneﬁt the most from Braille as the mode of education. Because Braille skills are more easily learned from 3 to 6 years of age, the decision to teach Braille must be made early.26 In children with markedly decreased vision, high-powered stand magniﬁers may be used for limited spot reading.

Conclusions Low vision rehabilitation in children is rewarding for the parents, the practitioner, and the child. Children with developmental glaucoma are visually rehabilitated best using a multidisciplinary approach, including teachers of visually impaired children, orientation and mobility instructors, low vision specialists, and parents. Because the disease affects children in their early developmental years, their eye care providers must help them make maximal use of their residual vision during these critical periods of development. Children with developmental glaucoma should not be labeled ‘blind’ because, in fact, they often have a good prognosis for retaining their vision. Even in the presence of progressive disease with a poor prognosis, children should be encouraged to use their residual vision.27 These rehabilitative services may be provided by the treating ophthalmologist or other professionals who manage children with low vision.

106

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INDEX

A A-scan ultrasound ocular biometry, 34, 72 acetazolamide, 59, 60 adrenergic agonists, 61–2 age choice of therapy and, 56 at onset, 5 vision testing and, 103–4 Ahmed Glaucoma Valve, 83, 84, 85 albinism, oculocutaneous, 43 Allen, L., 2 alpha-2 agonists, 61–2 ametropia, 104 amyloid, 36 amyloidosis, 35, 36 Anderson, J. Ringland, 1, 55 anesthesia, 31 examination under see examination under anesthesia intraocular pressure effects, 31–2 risks, 78 angiomatosis retinae, 6, 49, 50 angle, anterior chamber see anterior chamber angle angle-closure glaucoma in aphakia and pseudophakia, 94–5, 96 surgical treatment, 56, 87 aniridia, 8, 47–9 clinical features, 48–9 cyclocryotherapy complications, 86 differential diagnosis, 46, 49 embryologic basis, 16 genetics, 20–1 management of glaucoma, 49, 56 penetrating keratoplasty, 91 anisometropia, 29 anterior chamber angle abnormal development, 14–15 in aniridia, 48, 49 in Axenfeld–Rieger syndrome, 42 examination see gonioscopy histopathologic changes, 23–5 normal development, 12–14, 32 primordial endothelial layer see endothelial layer, primordial anterior chamber cleavage syndrome see Axenfeld–Rieger syndrome anterior ocular segment concepts of development, 11 normal development, 11–14 anticholinesterase drugs, 62 antifibrosis drugs in aphakia and pseudophakia, 99–100 in refractory pediatric glaucoma, 81–2, 83 antimetabolites see 5-fluorouracil; mitomycin-C aphakia and pseudophakia, glaucoma in, 6, 93–102 causes of delay in diagnosis, 95 diagnostic clues and evaluation, 98–9 mechanisms, 95–8 medical therapy, 62, 99 prevalence, 94

risk factors, 98 time interval to onset, 94–5 treatment, 99–101 vs. ocular hypertension, 93–4 apnea beta-blocker induced, 59 perioperative, 62, 77, 78 apraclonidine, 61 arachnoid cyst, congenital parasellar, 43 asthma, 59, 60 astigmatism, 28, 29, 104 ataxia–telangiectasia, 49 Axenfeld–Rieger syndrome (anterior chamber cleavage syndrome), 9, 41–6 clinical features, 42–3 differential diagnosis, 44–6 genetics, 20 histopathology, 24, 43 management, 46 pathogenesis, 15, 44–5 Peters anomaly and, 47 Axenfeld’s anomaly, 7, 8, 41 axial length of eye, 34, 72 B B-scan ultrasonography, 34 Baerveldt implants, 83, 84, 85 Barkan, Otto, 1, 65 Barkans goniotomy see goniotomy Barkans membrane, 1, 14, 23, 24 basal cell nevus syndrome, 49 beta-blockers, 59–60, 99 betaxolol, 59 bilateral surgery, simultaneous see simultaneous bilateral surgery bimatoprost, 59 binocularity, assessment, 104 birth trauma, 35 bleb-related infections, postoperative, 82 blepharospasm, 27, 30 blue-sclera appearance, 28, 29 Bourneville syndrome (tuberous sclerosis), 49, 50 Bowman’s membrane, in Peters anomaly, 47 Braille, 106 brimonidine, 61, 62 brinzolamide, 59 broad thumb syndrome, 6, 52 buphthalmos choice of therapy and, 57–8 defined, 5 historical descriptions, 1, 2 in primary congenital glaucoma, 28–9 see also ocular enlargement Burian, H.M., 2, 67 C capsulopupillary vessels, lateral, 16 carbonic anhydrase inhibitors, 59, 60–1 cardiopulmonary arrest, perioperative, 77, 78 107

Index cataract surgery glaucoma after, 93–102 simultaneous bilateral, 78 cataracts in aniridia, 48–9 Peters anomaly and, 47 Chandler’s syndrome, 44 chloral hydrate, 30 cholinergic drugs, 62 choroid, atrophy, 25 chromosomal anomalies, 52 chromosome 1q23–q25, 20 chromosome 6p25 mutations, 16 chromosome 11 deletion, 21 ciliary body abnormal development, 14, 15 atrophy, 25 histopathology, 24 normal development, 13 classification, 2, 6–9 anatomical (Hoskins et al), 2, 6–8 systems, 6–7 Cogan–Reese syndrome, 44 collagen, 23, 25 colobomas, 8, 48 combined trabeculotomy–trabeculectomy, 69–71 long-term outcome, 71 operative procedure, 69–70 postoperative care and follow up, 70–1 simultaneous bilateral, 78–9 in Sturge–Weber syndrome, 56 Congenital and Pediatric Glaucomas (Shaffer & Weiss), 2 congenital glaucoma, defined, 5 congenital hereditary endothelial dystrophy (CHED), 35, 37 congenital hereditary stromal dystrophy, 37 congenital rubella syndrome see maternal rubella syndrome conjunctivitis, 34–5 consanguinity, 19 contrast sensitivity, 105 corectopia in Axenfeld–Rieger syndrome, 43 in ectopia lentis et pupillae, 46 glaucoma drainage implants and, 85 in iridocorneal endothelial syndrome, 44 cornea in Axenfeld–Rieger syndrome, 42, 43 central lesions, 8, 46–7 development, 12 effects of elevated intraocular pressure, 25, 28 examination under anesthesia, 31 midperipheral lesions, 8 peripheral lesions, 8, 42 in Peters anomaly, 46–7 in primary congenital glaucoma, 23–4, 30 scarring, 25, 30 verticillata, 37 corneal clouding see corneal opacities corneal dermoid, 37 corneal diameter choice of therapy and, 57–8 enlargement see corneal enlargement measurement, 31, 72, 98 normal, 28 corneal dystrophies congenital hereditary endothelial, 35, 37 congenital hereditary stromal, 37 lattice, 36 Meesman’s, 35 posterior polymorphous (PPD), 37, 44, 45 Reis–Buckler, 35 108

corneal edema differential diagnosis, 35–8 in iridocorneal endothelial syndrome, 44 in primary congenital glaucoma, 28 corneal endothelium in Axenfeld–Rieger syndrome, 42 decompensation, 25, 90, 91 development, 12, 13 elevated intraocular pressure effects, 25, 28 in iridocorneal endothelial syndrome, 44 in posterior polymorphous dystrophy, 45 in primary congenital glaucoma, 24 see also endothelial layer, primordial corneal enlargement choice of therapy and, 57–8 differential diagnosis, 35 pathological effects, 25 in primary congenital glaucoma, 28 see also megalocornea corneal haze see corneal opacities corneal leukomas, congenital, 47 corneal opacities (and clouding) in aniridia, 48, 49 in Axenfeld–Rieger syndrome, 42 choice of therapy and, 57 differential diagnosis, 35–8 penetrating keratoplasty, 89–91 in Peters’ anomaly, 46–7 in primary congenital glaucoma, 28 corneal stroma development, 12 in primary congenital glaucoma, 23–4, 28 corneal transplantation, 89–91 corneal ulcer, Von Hippel’s internal, 47 corneodysgenesis, 2, 5 corneoiridotrabeculodysgenesis classification, 8 management, 56 cyclocryotherapy, 85–6, 101 cyclodestructive procedures in aphakia and pseudophakia, 101 in refractory glaucoma, 85–7 cyclodialyses, 77 cyclopentolate, 33 cyclophotocoagulation, 85, 86, 101 cyclopropane, 31 CYP1B1 gene mutations, 16, 20 cystinosis, 35, 36 cytochrome P4501B1 gene mutations, 16, 20 D de Vincentis’ operation, 1, 65 DeLuise–Anderson (1983) classification, 6 dental anomalies, 43, 46 dermoid, corneal, 35, 37 Descemet’s membrane, 12 in elevated intraocular pressure, 25, 28 in Peters’ anomaly, 46–7 in posterior polymorphous dystrophy, 45 rupture, in birth trauma, 35 developmental glaucomas classification, 6–9 defined, 5 embryologic basis, 11–17 epidemiology, 19 genetics, 19–21 historical perspective, 1–3 management, 55–8 pathology and pathogenesis, 23–6 terminology, 5–6

Index diffuse congenital hemangiomatosis, 49 digenic inheritance, 20 dipivefrin hydrochloride, 62 dorzolamide, 59, 60–1 double ring sign, 38 Down syndrome, 52 drainage implant surgery see glaucoma drainage implants Duke-Elder, Sir Stewart, 2 dysgenesis mesodermalis corneae et iridis see Axenfeld–Rieger syndrome E echothiophate iodide, 62 ectoderm, 11 ectopia lentis (lens subluxation) in aniridia, 48 in homocystinuria, 51 in primary congenital glaucoma, 30 ectopia lentis et pupillae, 46 ectropion uvea, congenital, 45–6 Edward syndrome, 52 embryologic basis, 11–17 embryonic fissure, 12 embryotoxon, posterior, 8, 41, 42 emmetropization, 34 empty sella syndrome, primary, 43 encephalotrigeminal angiomatosis see Sturge–Weber syndrome endophthalmitis, postoperative, 77–8, 79 endoscopic cyclophotocoagulation, 86 endoscopic goniotomy, 67 endothelial layer, primordial, 13–14 in Axenfeld–Rieger syndrome, 15, 44–5 in primary congenital glaucoma, 14, 23 see also Barkan’s membrane; corneal endothelium enucleation, 2 epidemiology, 19 epinephrine, 62, 99 epiphora (excessive tearing) differential diagnosis, 34–5 in primary congenital glaucoma, 27, 30 episcleral venous pressure, elevated, 25, 50–1, 56, 85 examination, initial, 30–1 examination under anesthesia (EUA), 31–4 in aphakia and pseudophakia, 98 at follow-up, 70, 71 interpretation of findings, 34 external trabeculotomy see trabeculotomy ab externo extracellular matrix, 14, 23, 25 eye enlargement see ocular enlargement F Fabry disease, 35, 37 facial anomalies, 43 facial hemiatrophy, 46 Fanconi syndrome, 51 filtration surgery in aphakia and pseudophakia, 87–100 in refractory glaucoma, 81–2, 83 in Sturge–Weber syndrome, 56–7 see also trabeculectomy FKHL7 gene see FOXC1 gene 5-fluorouracil (5-FU), 81, 99–100 follow-up after cataract surgery, 99 after glaucoma surgery, 71–2 forkhead transcription factor, 16, 20 founder effect, 19, 20 FOXC1 gene, 16, 20 FREAC3 gene see FOXC1 gene fundus photography, ocular, 33, 72

G genetic counseling, 21 genetics, 16, 19–21 germ-layer theory, 11 Gillespie’s syndrome, 21 glaucoma in aniridia, 48 in aphakia and pseudophakia see aphakia and pseudophakia, glaucoma in in Axenfeld–Rieger syndrome, 43, 45, 46 criteria for diagnosis, 93–4 in iridocorneal endothelial syndrome, 44, 45 in Peters’ anomaly, 47 in phakomatoses, 49–51 in posterior polymorphous dystrophy, 45 severity, choice of therapy and, 57 glaucoma drainage implants in aphakia and pseudophakia, 100 in refractory glaucoma, 83–5 Glaucoma in Infants and Children (Kwitko), 2 GLC3A, 19–20 GLC3B, 20 glucose-6-phosphate deficiency, 35, 37 glycerine, 62 glycerol, 62 glycoproteins, 14 Goldmann lens, 32 goniodysgenesis, 2, 5 gonioscopy, 30, 31, 32–3 in aphakia and pseudophakia, 98–9 in Axenfeld–Rieger syndrome, 42 in primary congenital glaucoma, 32–3 goniotomy, 65–7 endoscopic, 67 equipment, 65–6 history, 1, 2 mechanism of effect, 25 outcome, 66, 67 procedure, 66 simultaneous bilateral, 77 vs. trabeculotomy ab externo, 67, 68–9 growth hormone deficiency, 43 H Haab’s striae, 25, 28 Hallerman–Streiff syndrome, 49 halothane anesthesia, 31, 32 hamartias, 49 hamartomas, 49 Harms, H., 2 hemangioma, iris, 50 hemangiomatosis, diffuse congenital, 49 heparan sulfate proteoglycans, 14 heredity, 19 herpes simplex congenital or neonatal ocular, 35–6 iridocyclitis, 6 keratitis, 90 histopathology, 23–5, 43 historical perspective, 1–3 history, low vision, 103 homocystinuria, 6, 51, 57 Hoskins, Shaffer and Hetherington (1984) classification, 2, 6–7 Hunter syndrome, 36 Hurler syndrome, 36 hyaloid system, posterior, 15–16 hydrophthalmia defined, 5 historical descriptions, 1, 2, 55 Hydrophthalmia or Congenital Glaucoma (Anderson), 2 109

Index hyperopia, excessive loss, 98 hypoplastic iris syndrome, familial, 7 hypospadias, 43 hypotony, postoperative, 83, 85 I illumination, 104–5 India, 19, 20 infantile glaucoma, defined, 5–6 infants, ocular examination, 30–1 infections, postoperative, 82, 100 intraocular pressure defining glaucoma, 93, 94 effects of anesthesia, 31–2 elevated in aphakia and pseudophakia, 93–4, 95–8 causes, 25 differential diagnosis, 38 effects in infant eye, 25, 28–9 historical description, 1 medical therapy, 59–63 measurement, 30, 31–2, 72 normal infant, 32 iopidine, 62 iridectomy laser, 87 surgical, 87, 99 iridemia, 47 iridocorneal adhesions in Axenfeld–Rieger syndrome, 42, 43 in posterior polymorphous dystrophy, 45 iridocorneal angle see anterior chamber angle iridocorneal endothelial (ICE) syndrome, 44–5 iridocyclitis, 35 iridodialyses, 77 iridodysgenesis, 2, 7–8 anomalous iris vessels, 7–8 anterior stromal defects, 7 defined, 5 structural iris anomalies, 8 iridoschisis, 46 iridotomy, laser, 99 iridotrabeculodysgenesis classification, 7–8 management, 56 iris anomalous superficial vessels, 8 in Axenfeld–Rieger syndrome, 42, 43 development, 12, 13 elevated intraocular pressure effects, 25 embryologic basis of anomalies, 15–16 gonioscopic appearances, 33 holes, 8, 43 in iridocorneal endothelial syndrome, 44 pigment epithelial layer, 12 processes, 24 strands (adhesions), 42, 43 structural defects, 8 vascular anomalies, 7–8 iris atrophy, progressive (essential), 44 iris hypoplasia in aniridia, 48 anterior stroma, 7 congenital, 45 familial, with glaucoma, 7 iris insertion (into trabecular meshwork) abnormal development, 14, 15 anterior, 7, 23, 24, 32, 33 concave (wrap-around), 7, 32 flat, 7, 32 110

normal development, 13 normal infant eye, 32 in primary congenital glaucoma, 32, 33 iris nevus syndrome, 44 iris stroma abnormal development, 15–16 in Axenfeld–Rieger syndrome, 42, 43 hyperplasia of anterior, 7 hypoplasia of anterior, 7 normal development, 12 J Japan, 20 juvenile glaucoma, defined, 5 juvenile xanthogranuloma, 6 K keratitis, 35 keratoconus, posterior, 47 keratocytes, 12, 23 keratolenticular contact, and Peters’ anomaly, 47 keratolimbal allograft, 91 keratometry, 104 keratoplasty, penetrating see penetrating keratoplasty ketamine, 31 Klippel–Trenaunay–Weber syndrome, 49 knife, goniotomy, 65 Koeppe lens, 31, 32, 33 Krupin implants, 83, 84 L laser therapy, 55, 87 in aphakia and pseudophakia, 99 cyclophotocoagulation, 86, 101 latanoprost, 59, 61 lattice corneal dystrophy, 36 lens development, 12 elevated intraocular pressure effects, 25 opacities see cataracts subluxation see ectopia lentis thickness, in glaucoma, 34 vascular tunic, abnormal development, 15–16 lensectomy and vitrectomy, automated, 94 leukomas, congenital corneal, 47 levobunolol, 59 Lignae–Fanconi syndrome, 36 limbal stem cell transplantation, 91 Lister’s morning mist, 33 Loch Ness Monster phenomenon, 33 Louis–Bar syndrome, 49 low vision assessment, 103–5 devices, 105–6 see also visual impairment Lowe syndrome see oculocerebrorenal syndrome of Lowe M Mackay–Marg tonometer, 32 macular edema, cystoid, 62, 99 magnifiers, 105 management developmental glaucomas, 55–8 residual vision, 105–6 see also medical therapy; surgery, antiglaucoma mannitol, 62 Marfan syndrome, 2, 6, 49, 67 Maroteax–Lamy syndrome, 36 maternal rubella syndrome, 6, 8, 24, 25, 38 McPherson, Samuel D., Jr., 2

Index medical therapy, 55, 59–63 in aphakia and pseudophakia, 62, 99 Meesman’s corneal dystrophy, 35 megalocornea, 8 in Axenfeld–Rieger syndrome, 42 differential diagnosis, 35 X-linked recessive, 8 see also corneal enlargement membrane in Axenfeld–Rieger syndrome, 44–5 Barkan’s see Barkan’s membrane in iridocorneal endothelial syndrome, 44 mesenchyme, 11 mesodermal, 12 neural crest-derived, 11, 12 mesoderm, 11, 12 mesodermal dysgenesis of the cornea and iris see Axenfeld–Rieger syndrome metabolic diseases, 36–7, 51 metachromatic leukodystrophy, 37 microcornea, 8 in aniridia, 49 aphakic/pseudophakic glaucoma and, 97, 98 in Axenfeld–Rieger syndrome, 42 microscope, operating, 2, 66 microspherophakia, 6 microsurgery, 2 Microsurgery Study Group, International Symposia, 2 Middle East, 19, 20 miotic drugs, 62, 99 mitomycin-C in aphakic and pseudophakic glaucoma, 99–100 in primary glaucoma surgery, 70, 71 in refractory glaucoma, 81–2, 83, 85 mobility training, 106 Molteno implants, 83, 84, 85, 100 Morquio syndrome, 36 mucolipidoses, 35, 36 mucopolysaccharidoses (MPS), 35, 36 mydriasis, 33 MYOC gene, 20 myopia, 104, 105 differential diagnosis, 35, 38 miotic-induced, 62 in primary congenital glaucoma, 29, 34 N nanophthalmos, 8 nasolacrimal drainage system, obstruction, 34, 35 neural crest cells, 12 abnormal development, 14, 24 ocular derivatives, 11, 12 neurocristopathies, 9, 15 neurofibromatosis, 6, 15, 24, 46, 49, 50 nevoxanthoendothelioma, 6 nevus of Ota, 49, 50 nylon filament trabeculotomy, 2, 67 nystagmus, in aniridia, 49 O obstetric trauma, 35 ocular enlargement, 25 at follow-up, 72 in primary congenital glaucoma, 27, 28–9 ultrasonic biometry, 34 see also buphthalmos ocular hypertension vs. glaucoma, in aphakia and pseudophakia, 93–4 see also intraocular pressure, elevated oculocerebrorenal syndrome of Lowe, 6, 36, 51

glaucoma after cataract surgery, 93 management, 57 oculodentodigital dysplasia, 46 oculodermal melanocytosis (nevus of Ota), 6, 49, 50 Ocusert, 62 open-angle glaucoma, in aphakia and pseudophakia, 95, 96–8 ophthalmoscopy at follow-up, 71, 72 in primary congenital glaucoma, 33 optic cup developmental abnormalities, 16 formation, 12 optic disc congenital malformations, 35, 38 evaluation, 33 tilted, 35 optic (embryonic) fissure, 12 optic nerve abnormalities, differential diagnosis, 38 hypoplasia, 38, 49 in primary congenital glaucoma, 28, 33 optic nerve cupping, 25 cup-to-disc ratios, 33 follow-up, 72 physiologic, 33, 35, 38 in primary congenital glaucoma, 29–30, 33 reversibility, 29–30, 33 optic stalk, 11, 12 optic vesicle, 11, 12 orientation training, 106 osmotic drugs, 62 oxygen therapy, 51 P Patau’s syndrome (trisomy 13–15 syndrome), 6, 52 pathology/pathogenesis, 23–6 PAX6 gene, 21 pectinate ligament, 24 fetal, 13 penetrating keratoplasty, 89–92 in congenital glaucoma, 89–91 timing of glaucoma surgery, 91 Perkins hand-held applanation tonometer, 31, 32 persistent hyperplastic primary vitreous (PHPV), 6, 8, 16, 51 Peters’ anomaly, 8, 9, 46–7 clinicopathologic features, 46–7 differential diagnosis, 37–8, 45, 47 embryologic basis, 15 histopathological changes, 24 management, 47 phakomatoses, 9, 15, 49–51 phenylephrine, 33 phospholine iodide, 62 photography, ocular fundus, 33, 72 photophobia in aniridia, 48 illumination and, 104–5 in primary congenital glaucoma, 27, 30 Pierre Robin syndrome, 6 pilocarpine, 62, 99 pituitary gland anomalies, 43 posterior embryotoxon, 8, 41, 42 posterior keratoconus, 47 posterior polymorphous dystrophy (PPD), 37, 44, 45 Prader–Willi syndrome, 46 primary congenital glaucoma, 27–39 clinical features, 27–30 defined, 5–6 diagnostic examination, 30–4 differential diagnosis, 34–8 111

Index primary congenital glaucoma (cont’d) genetic counseling, 21 genetics, 16, 19–20 histopathological changes, 23–4 historical descriptions, 2 incidence, 19 management, 34, 55–6 pathogenesis, 13, 14–15, 23 trabeculotomy ab externo, 69 primary developmental glaucoma, 5 primary dysgenesis mesodermalis of the iris see Axenfeld–Rieger syndrome primary infantile glaucoma see primary congenital glaucoma prognosis, after surgery, 71–2 prostaglandin-related drugs, 59, 61 pseudophakia, glaucoma in see aphakia and pseudophakia, glaucoma in ptosis, 45–6, 49 pupillary block glaucoma, in aphakia and pseudophakia, 96, 99 pupillary membrane, 12, 15 persistent, 16

112

R reading aids, 105 red eye differential diagnosis, 34–5 in primary congenital glaucoma, 27 refractive errors in aniridia, 49 assessment, 31, 34, 104 correction, 105 at follow-up, 71 refractory pediatric glaucoma, 81–8 cyclodestructive procedures, 85–7 filtration surgery with antifibrosis drugs, 81–2, 83 glaucoma drainage implants, 83–5 laser therapy, 87 rehabilitation, visual, 72, 105–6 Reis–Buckler dystrophy, 35 respiratory failure, during anesthesia, 78 retina atrophy, 25 racemouse angioma, 49 retinoblastoma, 6 retinopathy of prematurity, 6, 24, 25, 51–2 retinoscopy, 104 retrolental fibroplasia see retinopathy of prematurity Richardson–Shaffer lens, 31 Rieger syndrome, 41 Rieger’s anomaly, 7, 8, 41 Roms, Slovakian, 19, 20 rubella congenital see maternal rubella syndrome keratitis, 35 Rubenstein–Taybi syndrome, 6, 52 rubeosis, 8

sclera, in primary congenital glaucoma, 28, 29 scleral spur normal development, 13 in primary congenital glaucoma, 33 rudimentary, 14, 15, 24 in trabeculotomy ab externo, 68 sclerocornea, 35 secondary developmental glaucoma, 41–53 defined, 5 histopathological changes, 24–5 trabeculotomy ab externo, 69 sedation, for ocular examination, 30 Shaffer–Weiss (1970) classification, 2, 6 short stature, 43 simultaneous bilateral surgery, 77–9 anesthetic risks, 78 clinical experience, 78–9 surgical risks, 77–8 skin, redundant periumbilical, 43 slit lamp examination, 32 Slovakian Roms, 19, 20 Sly syndrome, 36 Smith, Redmond, 2, 67 spectacles, 105 sphingolipidoses, 37 Staphylococcus infections, postoperative, 82 staphyloma anterior, 8, 15 congenital, 47 stereopsis, assessment, 104 strabismus, in Axenfeld–Rieger syndrome, 43 Sturge–Weber syndrome (encephalotrigeminal angiomatosis), 6, 9, 49, 50–1 embryologic basis, 15 histopathological changes, 24–5 medical therapy, 61 surgical treatment, 56–7, 71, 85 succinylcholine, 31, 62 sulfite oxidase deficiency, 51 surgery, antiglaucoma, 55 in aphakia and pseudophakia, 99–101 Axenfeld–Rieger syndrome, 46 factors influencing choice, 55–8 failure of initial, 81 initial, 34, 65–74 long-term follow-up and prognosis, 71–2 penetrating keratoplasty and, 91 in refractory glaucoma, 81–8 simultaneous bilateral, 77–9 see also specific procedures Swan–Jacob goniotomy lens, 65, 66 synechiae, peripheral anterior, 44 syphilis, congenital, 36 systemic syndromes, choice of therapy, 56–7

S Sanfilippo syndrome, 36 Saudi Arabia, 20 Scheie syndrome, 36 Schiotz tonometry, 32 Schlemm’s canal development, 13, 14 elevated intraocular pressure and, 25 lack of obstruction, 25 in primary congenital glaucoma, 23, 24 in secondary glaucomas, 24, 25 trabeculotomy ab externo procedure, 68 Schwalbe’s line development, 13 prominent, 24, 42, 43

T tearing, excessive see epiphora teeth defects, 43, 46 telescopes, 105 terminology, 5–6 TIGR/MYOC gene, 20 tilted disc syndrome, 35, 38 timolol, 59–60 tonometry, 31–2, 72 Tonopen tonometer, 31, 32 trabecular meshwork abnormal development, 14, 15 in Axenfeld–Rieger syndrome, 43 elevated intraocular pressure effects, 25 iris insertion see iris insertion

Index trabecular meshwork (cont’d) normal development, 13, 14 normal infant eye, 32 obstruction to aqueous flow, 25 in primary congenital glaucoma, 23, 24, 32 in secondary glaucomas, 24, 25 trabeculectomy in aphakia and pseudophakia, 99–100 primary, 69 in refractory glaucoma, 81–2, 83, 85 vs. combined trabeculotomy–trabeculectomy, 71 see also combined trabeculotomy–trabeculectomy trabeculodysgenesis, 2, 7 classification, 6–7 defined, 5 isolated, 5, 6, 7, 27, 55–6 trabeculoplasty, laser, 87, 99 trabeculotomes, 67, 69 trabeculotomy ab externo, 67–9 360º technique, 69 history, 2, 67 instruments, 67 outcome, 67, 69 procedure, 67–8 vs. combined trabeculotomy–trabeculectomy, 71 vs. goniotomy, 67, 68–9 see also combined trabeculotomy–trabeculectomy training, low vision, 105–6 travoprost, 59 trisomy 13, 57 trisomy 13–15 syndrome, 6, 52 trisomy 18, 52 trisomy 21, 52 tuberous sclerosis, 49, 50 tunica vasculosa lentis, persistence, 7–8 Turkey, 20 Turner syndrome, 52 tyrosinase, 16

U ultrasonic biomicroscopy (UBM), 34 ultrasonic ocular biometry, 34, 72 uveal tissue, development, 13, 14 uveitis in aphakia and pseudophakia, 96 chronic childhood, 57 V vision assessment, 71, 103–5 long-term outcomes, 72, 73 visual acuity testing, 103–4 visual field examination, 30, 72, 93, 98, 104 visual impairment, 73, 103–6 management, 105–6 severe, 106 vision assessment, 103–5 vitrectomy and lensectomy, automated, 94 vitreous, persistent hyperplastic primary, 6, 8, 16, 51 Von Gierke disease, 37 Von Hippel–Lindau syndrome (angiomatosis retinae), 6, 49, 50 Von Hippel’s internal corneal ulcer, 47 von Recklinghausen disease see neurofibromatosis W WAGR syndrome, 21 Weill–Marchesani syndrome, 6 Wilms’ tumor, 21, 48 Wyburn–Mason syndrome, 49 X xanthogranuloma, juvenile, 6 Z zebra bodies, 37 Zeiss Optical Instrument Company, 2

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